Aryl fused azapolycyclic compounds

ABSTRACT

This invention is directed to compounds of the formula (I):  
                 
 
     and their pharmaceutically acceptable salts, wherein R 1 , R 2 , and R 3  are as defined herein; intermediates for the synthesis of such compounds, pharmaceutical compositions containing such compounds; and methods of using such compounds in the treatment of neurological and psychological disorders.

BACKGROUND OF THE INVENTION

[0001] This application is a continuation of Ser. No. 09/514,002, filedFeb. 25, 2000, which was a continuation-in-part of Ser. No. 09/402,010,filed Sep. 28, 1999, which is a National Stage under §371 ofPCT/IB98/01813, filed Nov. 13, 1998 which claims the benefit of SerialNo. 60/070,245, filed Dec. 31, 1997.

[0002] This invention relates to aryl fused azapolycyclic compounds, asdefined more specifically by formula I below. Compounds of formula Ibind to neuronal nicotinic acetylcholine specific receptor sites and areuseful in modulating cholinergic function. Such compounds are useful inthe treatment of inflammatory bowel disease (including but not limitedto ulcerative colitis, pyoderma gangrenosum and Crohn's disease),irritable bowel syndrome, spastic dystonia, chronic pain, acute pain,celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder,depression, bipolar disorder, autism, sleep disorders, jet lag,amyotrophic lateral sclerosis (ALS), cognitive dysfunction,hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastricacid hypersecretion, ulcers, pheochromocytoma, progressive supranuclearpalsy, chemical dependencies and addictions (e.g., dependencies on, oraddictions to nicotine (and/or tobacco products), alcohol,benzodiazepines, barbiturates, opioids or cocaine), headache, migraine,stroke, traumatic brain injury (TBI), obsessive-compulsive disorder(OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia,dyslexia, schizophrenia, multi-infarct dementia, age-related cognitivedecline, epilepsy, including petit mal absence epilepsy, senile dementiaof the Alzheimer's type (AD), Parkinson's disease (PD), attentiondeficit hyperactivity disorder (ADHD) and Tourette's Syndrome.

[0003] The compounds of this invention may also be used in combinationwith an antidepressant such as, for example, a tricyclic antidepressantor a serotonin reuptake inhibiting antidepressant (SRI), in order totreat both the cognitive decline and depression associated with AD, PD,stroke, Huntington's chorea or traumatic brain injury (TBI); incombination with muscarinic agonists in order to stimulate both centralmuscarinic and nicotinic receptors for the treatment, for example, ofALS, cognitive dysfunction, age-related cognitive decline, AD, PD,stroke, Huntington's chorea and TBI; in combination with neurotrophicfactors such as NGF in order to maximize cholinergic enhancement for thetreatment, for example, of ALS, cognitive dysfunction, age-relatedcognitive decline, AD, PD stroke, Huntington's chorea and TBI; or incombination with agents that slow or arrest AD such as cognitionenhancers, amyloid aggregation inhibitors, secretase inhibitors, taukinase inhibitors, neuronal anti-inflammatory agents and estrogen-liketherapy.

[0004] Other compounds that bind to neuronal nicotinic receptor sitesare referred to in U.S. patent application Ser. No. 08/963,852, whichwas filed on Nov. 4, 1997. The foregoing application is owned in commonwith the present application, and is incorporated herein by reference inits entirety.

SUMMARY OF THE INVENTION

[0005] This invention relates to aryl fused azapolycyclic compounds ofthe formula

[0006] R¹ is hydrogen, (C₁-C₆)alkyl, unconjugated (C₃-C₆)alkenyl,benzyl, XC(═O)R¹³ or —CH₂CH₂—O—(C₁-C₄)alkyl;

[0007] R² and R³ are selected, independently, from hydrogen,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy, nitro, amino, halo, cyano,—SO_(q)(C₁-C₆)alkyl wherein q is zero, one or two, (C₁₋C₆)alkyamino-,[(C₁-C₆)alky]₂amino-, —CO₂R⁴, —CONR⁵R⁶, —SO₂NR⁷R, —C(═O)R¹³, —XC(═O)R¹³,aryl-(C₀-C₃)alkyl- or aryl-(C₀-C₃)alkyl-O—, wherein said aryl isselected from phenyl and naphthyl, heteroaryl-(C₀-C₃)alkyl- orheteroaryl-(C₀-C₃)alkyl-O—, wherein said heteroaryl is selected fromfive to seven membered aromatic rings containing from one to fourheteroatoms selected from oxygen, nitrogen and sulfur; X²(C₀-C₆)alkyl-and X²(C₁-C₆)alkoxy-(C₀-C₆)alkyl-, wherein X² is absent or X² is(C₁-C₆)alkylamino- or [(C₁-C₆)alkyl]₂amino-, and wherein the(C₀-C₆)alky- or (C₁-C₆)alkoxy-(C₀-C₆)alkyl- moieties of saidX²(C₀-C₆)alkyl- or X²(C₁-C₆)alkoxy-(C₀-C₆)alkyl- contains at least onecarbon atom, and wherein from one to three of the carbon atoms of said(C₀-C₆)alkyl- or (C₁-C₆)alkoxy-(C₀-C₆)alky- moieties may optionally bereplaced by an oxygen, nitrogen or sulfur atom, with the proviso thatany two such heteroatoms must be separated by at least two carbon atoms,and wherein any of the alkyl moieties of said (C₀-C₆)alkyl- or(C₁₋C₆)alkoxy-(C₀-C₆)alkyl- groups may be optionally substituted withfrom two to seven fluorine atoms, and wherein one of the carbon atoms ofeach of the alkyl moieties of said aryi-(C₀-C₃)alkyl- and saidheteroaryl-(C₀-C₃)alkyl- may optionally be replaced by an oxygen,nitrogen or sulfur atom, and wherein each of the foregoing aryl andheteroaryl groups may optionally be substituted with one or moresubstituents, preferably from zero to two substituents, independentlyselected from (C₁-C₆)alkyl optionally substituted with from one to sevenfluorine atoms, (C₁-C₆)alkoxy optionally substituted with from two toseven fluorine atoms, halo (e.g., chloro, fluoro, bromo or iodo),(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy, nitro, cyano, amino,(C₁-C₆)alkylamino-, [(C₁-C₆)alkyl]₂amino-, —CO₂R⁴, —CON R⁵R5, —SO₂NR⁷R⁸,—C(═O)R¹³ and —XC(═O)R ¹³;

[0008] or R² and R³ together with the carbons to which they areattached, form a four to seven membered monocyclic, or a ten to fourteenmembered bicyclic, carbocyclic ring that can be saturated orunsaturated, wherein from one to three of the non-fused carbon atoms ofsaid monocyclic rings, and from one to five of the carbon atoms of saidbicyclic rings that are not part of the benzo ring shown in formula I,may optionally and independently be replaced by a nitrogen, oxygen orsulfur, and wherein said monocyclic and bicyclic rings may optionally besubstituted with one or more substituents, preferably from zero to twosubstituents for the monocyclic rings and from zero to threesubstituents for the bicyclic rings, that are selected, independently,from (C₀-C₆)alkyl- or (C₁-C₆)alkoxy-(C₀-C₆)alkyl-, wherein the totalnumber of carbon atoms does not exceed six and wherein any of the alkylmoieties may optionally be substituted with from one to seven fluorineatoms; nitro, oxo, cyano, halo, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy,amino, (C₁-C₆)alkylamino-, [(C₁-C₆)alkyl]₂amino-, —CO₂R⁴, —CON R⁵R⁶,—SO₂NR⁷R⁸, —C(═O)R¹³, and —XC(═O)R¹³;

[0009] each R⁴, R⁵, R⁶, R⁷ R⁸ and R¹³ is selected, independently, fromhydrogen and (C₁-C₆) alkyl, or R⁵ and R⁶, or R⁷ and R⁸ together with thenitrogen to which they are attached, form a pyrrolidine, piperidine,morpholine, azetidine, piperazine, —N—(C₁-C₆)alkylpiperazine orthiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur isreplaced with a sulfoxide or sulfone; and

[0010] each X is, independently, (C₁-C₆)alkylene;

[0011] with the proviso that: (a) at least one of R¹, R² and R³ must bethe other than hydrogen, and (b) when R² and R³ are hydrogen, R¹ cannotbe hydrogen, (C₁-C₆)alkyl, or unconjugated (C₃-C₆)alkenyl, andpharmaceutically acceptable salts of such compounds.

[0012] Examples of possible heteroaryl groups within the definition ofR² and R³ are the following: thienyl, oxazoy, isoxazolyl, pyridyl,pyrimidyl, thiazolyl, tetrazolyl, isothiazolyl, triazolyl, imidazolyl,tetrazolyl, pyrrolyl and the following groups:

[0013] wherein one of R⁹ and R¹⁸ is hydrogen or (C₁-C₆)alkyl, and theother is a bond to the benzo ring of formula I.

[0014] Examples of compounds of this invention are compounds of theformula I and their pharmaceutically acceptable salts, wherein R² andR³, together with the benzo ring of formula I form a bicyclic ringsystem selected from the following:

[0015] wherein R¹⁰ and R¹⁷ are selected, independently, from hydrogen,(C₁-C₆)alkyl; and (C₁-C₆)alkoxy-(C₀-C₆)alkyl- wherein the total numberof carbon atoms does not exceed six and wherein any of the alkylmoieties may optionally be substituted with from one to seven fluorineatoms; nitro, cyano, halo, amino, (C₁-C₆)alkylamino-, [(C₁-C₆)alkyl]₂amino-, —CO₂R⁴, —CONR ⁵R⁶, —SO₂NR⁷R⁸, —C(═O)R¹³, —XC(═O)R¹³,phenyl and monocyclic heteroaryl wherein said heteroaryl is defined asR² and R³ are defined in the definition of compounds of the formula Iabove;

[0016] Other embodiments of this invention relate to compounds of theformula I and their pharmaceutically acceptable salts, wherein R² andR³, together with the benzo ring of formula I form a bicyclic ortricyclic ring system selected from the following:

[0017] wherein R¹⁰ and R¹⁷ are defined as above, and m is zero, one ortwo, and wherein one of the carbon atoms of ring A can optionally bereplaced with oxygen or N(C₁-C₆)alkyl.

[0018] Other embodiments of this invention relate to compounds of theformula I and their pharmaceutically acceptable salts, wherein neitherR² nor R³ is attached to the benzo ring of formula I via an oxygen atom.

[0019] Other embodiments of this invention relate to compounds of theformula I and their pharmaceutically acceptable salts, wherein R² and R³do not, together with the benzo ring of formula I, form a bicyclic ortricyclic ring system.

[0020] Other embodiments of this invention relate to compounds of theformula I wherein one or both of R² and R³ are —C(═O)R¹³, wherein R¹³ is(C₁-C₆)alkyl. Further embodiments of this invention relate to compoundsof the formula I wherein one or both of R² and R³ are —C(O)R¹³, whereinR¹³ is (C₁-C₆)alkyl or (C₁-C₃)alkyl optionally substituted with from oneto seven fluorine atoms. Other embodiments relate to compounds of theformula I wherein one of R² and R³ is CF₃, fluoro, cyano, (C₂-C₆)alkynylor C₂F₅.

[0021] Other further embodiments of the present invention relates tocompounds of formula I having the structure

[0022] wherein R¹ is as defined above; and R² and R³ are hydrogen,(C₁-C₆)alkyl optionally substituted with from one to seven fluorineatoms; —C(═O)(C₁-C₆)alkyl, cyano, hydroxy, nitro, amino, —O(C₁-C₆)alkylor halo;

[0023] with the proviso that R² and R³ can not both be hydrogen when R¹is hydrogen, (C₁-C₆)alkyl, or unconjugated (C₃-C₆)alkenyl.

[0024] Examples of specific compounds of the formula I are the followingcompounds, which, in the instances where there is a center or centers ofasymmetry in the molecule, may comprise a racemic mixture or the singleenantiomer:

[0025]5,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),9-trien-6-one;

[0026]6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10.)0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0027]2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-5-yl)-benzamide;

[0028]6-methyl-5-thia-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0029]6-methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0030]5,7,13-triazatetracyclo[9.3.1.0^(2,11).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0031]7-methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0032]6-methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0033]6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0034]7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0035]7-butyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0036] 6-methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0037]7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0038]6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0039]7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0040]6-methyl-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0041]6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0042] 5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(1 1),3,5,7,9-pentaene;

[0043]14-methyl-5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0044]5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0045]6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)pentadeca-2(10),3,6,8-tetraene;

[0046]7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),6,9-tetraene;

[0047] 4-methyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0048] 4-nitro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0049] 4-amino-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0050]N¹-[10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl]acetamide;

[0051] 4,5-dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0052]4,5-difluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0053] 4-chloro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0054]3-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-5-methyl-1,2,4-oxadiazole;

[0055] 10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ol;

[0056] 4,5-dichloro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0057]N⁴,N⁴-dimethyl-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonamide;

[0058] 4-(1-pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0059]1-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;

[0060]3-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0061]4-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0062] 3-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0063] 10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl cyanide;

[0064] 4-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0065]5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0066]6-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0067]7-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0068]7-ethyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0069]8-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0070]5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one;

[0071]6-chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0072]6-methoxy-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0073]6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0074] 5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one;

[0075]6-chloro-3-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0076] and pharmaceutically acceptable salts thereof.

[0077] Other embodiments compounds of the invention include but are notlimited to:

[0078]6-methyl-5,7-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;

[0079]6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;

[0080]5,7-dimethyl-6-oxo-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;

[0081]5,7-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;

[0082]5-oxo-6,13-diazatetracyclo(9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;

[0083]6-oxo-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;

[0084]6-methyl-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0085]7-dimethylamino-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0086]6,7-dioxo-5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,9-triene;

[0087] 5,8-dimethyl-6,7-dioxo-5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,9-triene;

[0088]5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;

[0089]5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;

[0090]4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0091]5-ethynyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;

[0092]5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;

[0093]4-ethynyl-5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0094]4-fluoro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0095]4-chloro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0096]5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;

[0097]4-ethynyl-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0098]4,5-bistrifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0099] and pharmaceutically acceptable salts thereof. Other embodimentsof the invention are the hydrochloride salts of the above enumeratedcompounds.

[0100] This invention also relates to compounds of the formula

[0101] wherein P is hydrogen, methyl, COOR¹⁶ wherein R¹⁶ is(C₁-C₆)alkyl, allyl, 2,2,2-trichloroethyl or (C₁-C₆)alkyl; —C(═O)NR⁵R⁶wherein R⁵ and R⁶ are defined as in formula I above; —C(═O)H,—C(═O)(C₁-C₆)alkyl wherein the alkyl moiety may optionally besubstituted with from 1 to 3 halo atoms, preferably with from 1 to 3fluoro or chloro atoms; benzyl or t-butoxycarbonyl (t-Boc); and R¹⁴ andR¹⁵ are selected, independently, from hydrogen, (C₁-C₆)alkyl optionallysubstituted with from one to seven fluorine atoms; —C(═O)(C₁-C₆)alkyl,cyano, hydroxy, nitro, amino, —O(C₁-C₆)alkyl or halo; with the provisothat R¹⁴ and R¹⁵ can not both be hydrogen when P is hydrogen,(C₁-C₆)alkyl, or unconjugated (C₃-C₆)alkenyl. Such compounds are usefulas intermediates in the synthesis of compounds of the formula I.

[0102] The invention also relates to compounds of the formula:

[0103] wherein R² and R³ are defined above; and P′ is COOR¹⁶ wherein R¹⁶is allyl, 2,2,2-trichloroethyl or (C₁-C₆)alkyl; —C(═O)NR⁵R⁶ wherein R⁵and R⁶ are also as defined above; —C(═O)H, —C(═O)(C₁-C₆)alkyl whereinthe alkyl moiety may optionally be substituted with from 1 to 3 haloatoms, preferably with from 1 to 3 fluoro or chloro atoms; benzyl, ort-butoxycarbonyl.

[0104] Unless otherwise indicated, the term “halo”, as used herein,includes fluoro, chloro, bromo and iodo.

[0105] Unless otherwise indicated, the term “alkyl”, as used herein,includes straight chain moieties, and where the number of carbon atomssuffices, branched and cyclic moieties.

[0106] The term “alkoxy”, as used herein, means “—O-alkyl” or“alkyl-O-”, wherein “alkyl” is defined as above.

[0107] The term “alkylene”, as used herein, means an alkyl radicalhaving two available bonding sites (i.e., -alkyl-), wherein “alkyl” isdefined as above.

[0108] Unless otherwise indicated, the term “one or more substituents”,as used herein, refers to from one to the maximum number of substituentspossible based on the number of available bonding sites.

[0109] The term “treatment”, as used herein, refers to reversing,alleviating, inhibiting the progress of, or preventing the disorder orcondition to which such term applies, or one or more symptoms of suchcondition or disorder. The term “treatment”, as used herein, refers tothe act of treating, as “treating” is defined immediately above.

[0110] The compounds of formula I may have optical centers and thereforemay occur in different enantiomeric configurations. The inventionincludes all enantiomers, diastereomers, and other stereoisomers of suchcompounds of formula I as well as racemic and other mixtures thereof.

[0111] Particularly, preferred enantiomers of the invention include:

[0112](+)-5,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),9-trien-6-one;

[0113](+)-6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0114](+)-2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-5-yl)-benzamide;

[0115](+)-6-methyl-5-thia-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0116](+)-6-methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0117](+)-7-methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0118](+)-6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0119](+)-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0120](+)-7-butyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0121](+)-6-methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0122](+)-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0123](+)-6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0124](+)-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0125](+)-6-methyl-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0126](+)-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0127](+)-6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0128](+)-7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),6,9-tetraene;

[0129](+)-4-methyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0130] (+)-4-nitro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0131] (+)-4-amino-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0132](+)-N¹-[10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl]acetamide;

[0133] (+)-4-chloro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0134](+)-3-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-5-methyl-1,2,4-oxadiazole;(+)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ol;

[0135](+)-N⁴,N⁴-dimethyl-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonamide;

[0136] (+)-4-(1-pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0137](+)-1-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;

[0138](+)-3-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0139](+)-4-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0140](+)-3-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0141] (+)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ylcyanide;

[0142](+)-4-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0143](+)-6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;

[0144](+)-5-oxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;

[0145](+)-6-methyl-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0146](+)-7-dimethylamino-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0147](+)-5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;

[0148](+)-5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;

[0149](+)-4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0150](+)-5-ethynyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;

[0151](+)-5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;

[0152](+)-4-ethynyl-5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0153](+)-4-fluoro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0154](+)-4-chloro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0155](+)-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;

[0156](+)-4-ethynyl-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0157](+)-5,14-diazatetracyclo[1.0.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0158](+)-6-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0159](+)-7-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0160](+)-7-ethyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0161](+)-8-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0162](+)-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one;

[0163](+)-6-chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0164](+)-6-methoxy-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0165](+)-6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)hexadeca-2(11),3,5,7,9-pentaene;

[0166](+)-5,8,14-triazatetracyclo(10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one;

[0167] (+)-6-chloro-3-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0168] and pharmaceutically acceptable salts thereof.

[0169] In addition, other preferred enantiomers of the compounds of theinvention include:

[0170](−)-5,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),9-trien-6-one;

[0171](−)-6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0172](−)-2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-5-yl)-benzamide;

[0173](−)-6-methyl-5-thia-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0174](−)-6-methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0175](−)-7-methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0176](−)-6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0177](−)-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0178](−)-7-butyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0179](−)-6-methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0180](−)-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0181](−)-6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0182](−)-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0183](−)-6-methyl-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;

[0184](−)-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0185](−)-6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0186](−)-7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0^(2,1.0).0^(4,8)]pentadeca-2,4(8),6,9-tetraene;

[0187](−)-4-methyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0188] (−)-4-nitro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0189] (−)-4-amino-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0190](−)-N¹-[10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl]acetamide;

[0191] (−)-4-chloro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0192](−)-3-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-5-methyl-1,2,4-oxadiazole;

[0193] (−)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ol;

[0194](−)-N⁴,N⁴-dimethyl-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonamide;

[0195](−)-4-(1-pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0196](−)-1-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;

[0197](−)-3-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0198](−)-4-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0199](−)-3-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0200] (−)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ylcyanide;

[0201](−)-4-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0202](−)-6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;

[0203](−)-5-oxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;

[0204](−)-6-methyl-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0205](−)-7-dimethylamino-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;

[0206](−)-5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;

[0207](−)-5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;

[0208](−)-4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0209](−)-5-ethynyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;

[0210](−)-5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;

[0211](−)-4-ethynyl-5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0212](−)-4-fluoro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0213](−)-4-chloro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0214](−)-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;

[0215](−)-4-ethynyl-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;

[0216](−)-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,8)]hexadeca-2(11),3,5,7,9-pentaene;

[0217](−)-6-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0218](−)-7-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0219](−)-7-ethyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0220](−)-8-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0221](−)-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one;

[0222](−)-6-chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0223](−)-6-methoxy-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0224](−)-6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0225](−)-5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,tetraen-6-one;

[0226](−)-6-chloro-3-fluoro-5,14-diazatetracyclo[10.3.10^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

[0227] and pharmaceutically acceptable salts thereof.

[0228] The present invention also relates to all radiolabeled forms ofthe compounds of the formula I. Preferred radiolabeled compounds offormula I are those wherein the radiolabels are selected from as ³H, C,¹¹C, ¹⁴C, ¹⁸F, ¹²³I and ¹²⁵I. Such radiolabeled compounds are useful asresearch and diagnostic tools in metabolism studies, such aspharmacokinetics studies, etc., and in binding assays in both animalsand man.

[0229] The present invention also relates to a pharmaceuticalcomposition for use in reducing nicotine addiction or aiding in thecessation or lessening of tobacco use in a mammal, including a human,comprising an amount of a compound of the formula I or apharmaceutically acceptable salt thereof, that is effective in reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse and a pharmaceutically acceptable carrier.

[0230] The present invention also relates to a method for reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse in a mammal, including a human, comprising administering to saidmammal an amount of a compound of the formula I or a pharmaceuticallyacceptable salt thereof, that is effective in reducing nicotineaddiction or aiding in the cessation or lessening of tobacco use.

[0231] The present invention also relates to a method of treating adisorder or condition selected from inflammatory bowel disease(including but not limited to ulcerative colitis, pyoderma gangrenosumand Crohn's disease), irritable bowel syndrome, spastic dystonia,chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction,anxiety, panic disorder, depression, bipolar disorder, autism, sleepdisorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitivedysfunction, hypertension, bulimia, anorexia, obesity, cardiacarrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma,progressive supranuclear palsy, chemical dependencies and addictions(e., dependencies on, or addictions to nicotine (and/or tobaccoproducts), alcohol, benzodiazepines, barbiturates, opioids or cocaine),headache, migraine, stroke, traumatic brain injury (TBI),obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea,tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarctdementia, age-related cognitive decline, epilepsy, including petit malabsence epilepsy, senile dementia of the Alzheimer's type (AD),Parkinson's disease (PD), attention deficit hyperactivity disorder(ADHD) and Tourette's Syndrome in a mammal, comprising administering toa mammal in need of such treatment an amount of a compound of theformula I or a pharmaceutically acceptable salt thereof, that iseffective in treating such disorder or condition.

[0232] The present invention also relates to a pharmaceuticalcomposition for treating a disorder or condition selected frominflammatory bowel disease (including but not limited to ulcerativecolitis, pyoderma gangrenosum and Crohn's disease), irritable bowelsyndrome, spastic dystonia, chronic pain, acute pain, celiac sprue,pouchitis, vasoconstriction, anxiety, panic disorder, depression,bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateralsclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia,obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers,pheochromocytoma, progressive supranuclear palsy, chemical dependenciesand addictions (e.g., dependencies on, or addictions to nicotine (and/ortobacco products), alcohol, benzodiazepines, barbiturates, opioids orcocaine), headache, migraine, stroke, traumatic brain injury (TBI),obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea,tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarctdementia, age-related cognitive decline, epilepsy, including petit malabsence epilepsy, senile dementia of the Alzheimer's type (AD),Parkinson's disease (PD), attention deficit hyperactivity disorder(ADHD) and Tourette's Syndrome in a mammal, comprising an amount of acompound of the formula I or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

[0233] The present invention also relates to a method for reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse in a mammal, comprising administering to said mammal an amount of acompound comprising an amount of a compound of the formula

[0234] wherein R¹⁹ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, or unconjugated (C₃-C₆)alkenyl, or a pharmaceuticallyacceptable salt thereof, that is effective in reducing nicotineaddiction or aiding in the cessation or lessening of tobacco use.

[0235] The present invention also relates to a method for treating adisorder or condition selected from inflammatory bowel disease(including but not limited to ulcerative colitis, pyoderma gangrenosumand Crohn's disease), irritable bowel syndrome, spastic dystonia,chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction,anxiety, panic disorder, depression, bipolar disorder, autism, sleepdisorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitivedysfunction, hypertension, bulimia, anorexia, obesity, cardiacarrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma,progressive supranuclear palsy, chemical dependencies and addictions(e., dependencies on, or addictions to nicotine (and/or tobaccoproducts), alcohol, benzodiazepines, barbiturates, opioids or cocaine),headache, migraine, stroke, traumatic brain injury (TBI),obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea,tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarctdementia, age-related cognitive decline, epilepsy, including petit malabsence epilepsy, senile dementia of the Alzheimer's type (AD),Parkinson's disease (PD), attention deficit hyperactivity disorder(ADHD) and Tourette's Syndrome in a mammal, comprising administering toa mammal in need of such treatment an amount of a compound of theformula

[0236] where R¹⁹ is defined above, or a pharmaceutically acceptable saltthereof, that is effective in treating such disorder or condition.

[0237] This invention also relates to the pharmaceutically acceptableacid addition salts of the compounds of formula I. Examples ofpharmaceutically acceptable acid addition salts of the compounds offormula I are the salts of hydrochloric acid, p-toluenesulfonic acid,fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid,hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid,malic acid, di-p-toluoyl tartaric acid, and mandelic acid, as well saltsformed from other acids known to those of skill in the art to formpharmaceutically acceptable acid addition salts to basic compounds.Other possible acid addition salts are, e.g., salts containingpharmaceutically acceptable anions, such as the hydroiodide, nitrate,sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate,gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate) salts).

[0238] The present invention also relates to methods for the preparationof the novel compounds of formula I. The invention is directed to aprocess for the preparation of a compound of formula IA:

[0239] wherein R¹⁰ is defined above, comprising the step of reacting acompound of formula VI:

[0240] wherein Q is a nitrogen protecting group, with a compound offormula XXIIB:

[0241] wherein R²⁰ and R²¹ are each independently (C₁-C₆)alkyl, andwherein R¹⁰ is defined above; and

[0242] (ii) removing the protecting group Q.

[0243] The nitrogen protecting group Q may be chosen from suitablegroups known to those of skill in the art including —COCF₃, —COCCI₃,—COOCH₂CCl₃, —COO(C₁-C₆)alkyl and —COOCH₂C₆H₅. These groups may be addedor removed by methods described for each in T. W. Greene and G. M. Wuts,Protective Groups in Organic Synthesis (John Wiley & Sons, New York,1991). Preferably, the nitrogen protecting group Q is a trifluoroacetylor a t-butoxycarbonyl group.

[0244] The invention also relates to a process for the preparation of acompound of formula IB:

[0245] wherein R¹⁰ and R¹⁷ are defined above, comprising the steps of

[0246] (i) of reacting a compound of formula VI:

[0247] wherein Q is a nitrogen protecting group, with a compound offormula XXIIB:

[0248] wherein R²⁰ and R²¹ are each independently (C₁-C₆)alkyl, andwherein R¹⁰ is defined above; and

[0249] (ii) allowing the product of step (i) to react with a compound ofthe formula R¹⁷Z, wherein R¹⁷ is defined above, and Z is a leavinggroup, in the presence of a base;

[0250] (iii) removing the protecting group Q.

[0251] Preferably, in this method to prepare IB the leaving group isselected from the group consisting of halo, halosulfonate, mesylate andtosylate, and the base is an alkali metal hydride, hydroxide orcarbonate. Preferably, the protecting group Q is a trifluoroacetyl or at-butoxycarbonyl group.

[0252] The invention also relates to another process for the preparationof a compound of formula IB:

[0253] wherein R¹⁰ and R¹⁷ are defined above, comprising the steps of

[0254] (i) of reacting a compound of formula XXIIIA:

[0255] wherein Q is a nitrogen protecting group, with a compound offormula XXIIB:

[0256] wherein R²⁰ and R²¹ are each independently (C₁-C₆)alkyl, andwherein R¹⁰ is defined above; and

[0257] (iii) removing the protecting group Q.

[0258] Preferably, in this method to prepare IB, the protecting group Qis a trifluoroacetyl or a t-butoxycarbonyl group.

[0259] The invention is also directed to a process for preparing acompound of formula IC

[0260] wherein R¹⁰ and R¹⁷ are as defined above, comprising the steps of

[0261] (i) allowing a compound of formula VI:

[0262] wherein Q is a nitrogen protecting group, to react with acompound of formula

[0263] wherein Y is an alkali metal or alkaline earth metal cation; or acompound of formula

[0264] wherein R¹⁰ and R¹⁷ are as defined above; and

[0265] (ii) removing the protecting group Q.

[0266] The protecting group Q is preferably a trifluoroacetate group ora t-butoxycarbonyl group. Preferably, step (i) is conducted in a polarsolvent, more preferably, water, THF, DMF, DMSO, a mixture of water andany of THF, DMF or DMSO. In addition, the processes to make each ofcompounds IA, IB and IC, preferably comprise the further step ofreducing the nitro groups of a compound of formula IIC:

[0267] wherein Q is a nitrogen protecting group to form a compound offormula VI

[0268] More preferably, the reduction is conducted in the presence ofhydrogen gas employing a palladium catalyst. Preferably, the protectinggroup Q is a trifluoroacetyl or a t-butoxycarbonyl group.

[0269] The invention is also directed to a process for the preparationof a compound of formula IE:

[0270] wherein R¹⁰ is defined above, comprising the steps of

[0271] (i) reducing the nitro group of a compound of formula VIIIA

[0272] wherein Q is a nitrogen protecting group;

[0273] (ii) allowing the amino product to react with an acid chloride ofthe formula R¹⁰COCl or an acid anhydride of the formula (R¹⁰CO)₂Owherein R¹⁰ is (C₁-C₆)alkyl, or a compound of the formulaR¹⁰C((C₁-C₆)alkoxy)₃;

[0274] (iii) removing the protecting group Q.

[0275] Preferably, in this process to prepare IE, the reduction of step(i) is conducted by hydrogenation with a palladium or platinum catalyst.Preferably, the protecting group Q is a trifluoroacetyl or at-butoxycarbonyl group.

[0276] The invention is further related to a process for the preparationof a compound of formula IF:

[0277] wherein R¹⁰ is as defined above; comprising the steps of

[0278] (i) allowing a compound of formula XA:

[0279] wherein R¹⁰ is as defined above, and Q is a nitrogen protectinggroup, to react with Lawesson's reagent;

[0280] (ii) allowing the product of step (i) to react with potassiumferricyanide and sodium hydroxide;

[0281] (iii) removing the protecting group Q.

[0282] Preferably, the protecting group Q is a trifluoroacetyl or at-butoxycarbonyl group.

[0283] The invention also relates to a process for preparing compoundsthe formula:

[0284] wherein R² and R³ are defined above; comprising the steps of

[0285] (i) subjecting a compound of formula XIIIB:

[0286] to ozonolysis conditions;

[0287] (ii) partially reducing the resulting ozonide product of step (i)to a dialdehyde or product of equivalent oxidation state;

[0288] (iii) allowing the product of step (ii) to react with anarylmethylamine; and

[0289] (iv) removing the aryImethy group.

[0290] The ozonolysis conditions used may be any of those known to thoseof skill in the art. Preferably, the ozonolysis conditions are ozone inmethanol or dichloromethane, preferably methanol. In step (ii), thereduction of the ozonolysis product or ozonide is preferably conductedby hydrogenation, e.g., in the presence of hydrogen gas and a platinumor palladium catalyst with or without carbon/charcoal. Thearylmethylamine employed in step (iii) is benzyiamine,4-methoxybenzylamine or 3,4-dimethoxybenzylamine, preferablybenzylamine, and is preferably added in the presence of an acidcatalyst, preferably formic acid. The removal of the arylmethyl group instep (iv) is preferably a hydrogenolysis reaction conducted, e.g., inthe presence of hydrogen gas and a platinum or palladium catalyst withor without carbon/charcoal, and in the presence of an acid catalyst.

[0291] The invention also relates to a novel process for the preparationof a compound of formula

[0292] comprising the steps of

[0293] (i) hydrogenating a compound having the formula XXVIII orXXVIII′:

[0294] wherein R² and R³ are defined above;

[0295] (ii) cyclizing the amine-ester compound of formula XXIX

[0296] obtained from step (i) to form a lactam ring compound of formulaXXX

[0297] (iii) reducing the carbonyl moiety.

[0298] The preferred starting material in step (i) is thetrimethylsiloxy compound. The hydrogenation of step (i) is preferablyconducted with a palladium or platinum catalyst under hydrogen gas,preferably in the presence of an acid catalyst. The lactam formation ofstep (ii) is preferably performed in the presence of a base, preferablyan alkoxyalkalide compound in a nonaqueous protic solvent, morepreferably sodium tert-butoxide in methanol. The reduction of step (iii)is preferably performed in the presence of a borane tetrahydrofurancomplex, diborane, borane dimethysulfide complex, lithium aluminumhydride or a combination of sodium borohydride and boron trifluoride,more preferably a combination of sodium borohydride and borontrifluoride.

DETAILED DESCRIPTION OF THE INVENTION

[0299] Except where otherwise stated, R¹ through R¹⁹, m, P and P′, andstructural formula I in the reaction schemes and discussion that followare defined as above. Schemes 1-10, below, illustrate methods ofsynthesizing compounds of the formula I.

[0300] Referring to Scheme 1, the starting material of formula III isreacted with trifluoroacetic anhydride, in the presence of pyridine, toform the compound of formula IV. This reaction is typically conducted inmethylene chloride at a temperature from about 0° C. to about roomtemperature. Other methods of generating a trifluoroacetate protectinggroup that may be used are recognized by those of skill in the art.

[0301] The compound of formula IV is then converted into the dinitroderivative of formula IIA by the following process. The compound of theformula IV is added to a mixture of 4 or more equivalents oftrifluoromethanesulfonic acid (CF₃SO₂OH) and 2 to 3 equivalents ofnitric acid, in a chlorinated hydrocarbon solvent such as chloroform,dichloroethane (DCE) or methylene chloride. The resulting mixture isallowed to react for about 5 to 24 hours. Both of the foregoingreactions are generally conducted at a temperature ranging from about−78° C. to about 0° C. for about 2 hours, and then allowed to warm toroom temperature for the remaining time.

[0302] Reduction of the compound of formula IIA, using methods wellknown to those of skill in the art, yields the compound of formula IIB.This reduction can be accomplished, for example, using hydrogen and apalladium catalyst such as palladium hydroxide or palladium on carbonand running the reaction in methanol at about room temperature. Thesteps of Scheme 1 can also be performed with a nitrogen-protectinggroup, other than an a trifluoroacetyl group, that would be deemedsuitable by those of skill in the art. Other suitable nitrogenprotecting groups that can be used in the procedures describedthroughout this document include —COCF₃, —COCCl₃, —COOCH₂CCl₃,—COO(C₁-C₆)alkyl and —COOCH₂C₆H₅. These groups may be added or removedby methods described for each in T. W. Greene and G. M. Wuts, ProtectiveGroups in Organic Synthesis (John Wiley & Sons, New York, 1991).

[0303] Referring to Scheme 2, the compound of formula IIA is convertedinto the corresponding compound wherein the trifluoroacetyl protectinggroup is replaced by a t-Boc protecting group (VIA) by reacting it firstwith an alkali metal or alkaline earth metal (or ammonium) hydroxide orcarbonate, and then reacting the isolated product from the foregoingreaction with di-t-butyldicarbonate. Although t-Boc is used in thisinstance, other appropriate nitrogen-protecting groups known to those ofskill in the art may be used. The reaction with the alkali or alkalineearth metal (or ammonium) hydroxide or carbonate is generally carriedout in an aqueous alcohol, dioxane or tetrahydrofuran (THF) at atemperature from about room temperature to about 70° C., preferably atabout 70° C., for about one to about 24 hours. The reaction of theisolated, unprotected amine or an acid addition salt of such amine, fromthe above reaction with di-t-butyidicarbonate is preferably carried outin a solvent such as THF, dioxane or methylene chloride at a temperaturefrom about 0° C. to about room temperature. This reaction may or may notbe conducted in the presence of a base. When the reactant is a salt ofthe amine, use of a base is preferred. The resulting compound of formulaVIA can be converted into the corresponding diamino derivative offormula VIB using the procedure described above for converting thedinitro compound of formula IIA into the corresponding diamino compoundof formula IIB, or other generally accepted nitro group reductionmethods known to those of skill in the art, e.g., zinc-, tin-, oriron-mediated reductions, etc.

[0304] The conversion of the compound of formula VIB into the desiredcompound of the formula VlI can be accomplished by reacting the compoundof formula VIB with a compound of the formula XXIIA

[0305] wherein R¹⁰ is hydrogen, (C₁-C₆)alkyl optionally substituted withfrom one to seven fluorine atoms, aryl-(C₀ -C₃)alkyl wherein said arylis selected from phenyl and naphthyl, or heteroaryl-(C₀-C₃)alkyl whereinsaid heteroaryl is selected from five to seven membered aromatic ringscontaining from one to four heteroatoms selected from oxygen, nitrogenand sulfur, and wherein each of the foregoing aryl and heteroaryl groupsmay optionally be substituted with one or more substituents, preferablyfrom zero to two substituents, independently selected from (C₁-C₆)alkyloptionally substituted with from one to seven fluorine atoms,(C₁-C₆)alkoxy optionally substituted with from one to seven fluorineatoms and cyano. The preferred solvent for this reaction is a 10:1mixture of ethanol/acetic acid. The reaction temperature can range fromabout 40° C. to about 100° C. It is preferably about 60° C. Otherappropriate solvents include acetic acid, ethanol and isopropanol.

[0306] Alternate methods of preparing compounds of the formula VlI thecompound of formula VIB are described by Segelstein et al., TetrahedronLett., 1993, 34, 1897.

[0307] Removal of the t-Boc protecting group from the compound offormula VII yields corresponding compound of formula IA. The protectinggroup can be removed using methods well known to those of skill in theart. For example, the compound of formula VII can be treated with ananhydrous acid such as hydrochloric acid, hydrobromic acid,methanesulfonic acid, or trifluoroacetic acid, preferably hydrochloricacid in ethyl acetate, at a temperature from about 0° C. to about 100°C., preferably from about room temperature to about 70° C., for aboutone to 24 hours.

[0308] The compound of formula VII can be converted into thecorresponding compound of formula IB by reacting it with a compound ofthe formula R¹⁷Z, wherein R¹⁷ is defined as R¹⁰ is defined above, and Zis a leaving group such as a halo or sulfonate (e.g., chloro, bromo,mesylate or tosylate), in the presence of a base such as an alkali metalhydride, hydroxide or carbonate, preferably potassium hydroxide, in apolar solvent such as water, dimethylsulfoxide (DMSO), THF or DMF,preferably a mixture of DMSO and water, and then removing the protectinggroup as described above. The reaction with R¹⁷Z is generally carriedout at a temperature from about room temperature to about 100° C.,preferably at about 50° C., for about five hours.

[0309] Scheme 3 illustrates an alternate method of preparing compoundsof the formula IB from the compound of formula VIA. This method is thepreferred method of making compounds of the formula IB wherein R¹⁷ is abulky group such as an aryl or heteroaryl containing group, or when R¹⁷can not be attached, as illustrated in Scheme 2, by alkylation or arylsubstitution methods. Referring to Scheme 3, the compound of formula VIAis reacted with the appropriate compound of formula R¹⁷NH₂ in a polarsolvent such as THF, DMF or DMSO, preferably THF, at a temperature fromabout room temperature to about 100° C., preferably at the refluxtemperature, for about four to eighteen hours. The resulting compound offormula XXIII is then converted into the corresponding compound of theformula XXIV by reducing the nitro group to an amino group using methodswell known to those of skill in the art. Such methods are referred toabove for the conversion of the compounds of the formula IIA into acompound of the formula IIB in Scheme 1, and exemplified in experimentalExamples 12B and 18B. Closure to the imidazole ring to form thecorresponding compound of formula XXV can then be accomplished byreacting the compound of formula XXIV from the above reaction with acompound of the formula XXIIA:

[0310] wherein R¹⁰ is defined as above, as described above forconverting compounds of the formula VIB into those of the formula VII.

[0311] Removal of the protecting group from the compound of formula XXVyields the corresponding compound of formula IB. This can beaccomplished using methods well known in the art, for example, asdescribed above for forming compounds of the formula IA from thecorresponding compounds of the formula VII.

[0312] Scheme 4 illustrates a method of preparing compounds of theformula IC, wherein R¹⁰ and R¹⁷ are as defined above. Referring toScheme 4, the compound of formula VIB, or analogously formula IIB inScheme I, is reacted with a compound of the formula

[0313] (sodium bisulfite ethane dione addition adduct) in water oranother polar solvent such as THF, DMF or DMSO, preferably a mixture ofwater and a water miscible solvent such as THF, for about one to fourhours. The reaction temperature can range from about 40° C. to about100° C., and is preferably at about the reflux temperature.

[0314] Alternatively, the compound of formula VIB can be reacted with acompound of the formula

[0315] (double condensation reaction) in a polar solvent such as THF,water, or acetic acid, preferably a mixture of water and THF. Thisreaction is typically carried out at a temperature from about 40° C. toabout 100° C., preferably at the reflux temperature, for about two tofour hours. The desired quinoxoline of formula IC can then be formed bydeprotecting the compound formed in either of the foregoing reactions,using the method described above for converting a compound of theformula VII into one of the formula IA. Alternatively, in place ofcompound VIB in Scheme 4, the compound IIB of Scheme 1 may be usedanalogously in this procedure with deprotection/reprotection as outlinedin Scheme 2 (i.e., the process of transforming IIA to VIA) in order toarrive at ultimately the compound IC. In general, alternative nitrogenprotection groups are equally suited to the procedure of Scheme 4.

[0316] Scheme 5 illustrates a method of preparing compounds of theformula I wherein R² and R³, together with the benzo ring to which theyare attached, form a benzoxazole ring system. Such a compound, whereinR¹ is hydrogen, is depicted in Scheme 5 as chemical formula IE.Referring to Scheme 5, the compound of formula XXII, wherein Y is nitro,halo, trifluoromethanesulfonate or a diazonium salt, is reacted withpotassium acetate or another alkali or alkaline earth metal carboxylatein a solvent such as dimethylsulfoxide (DMSO), DMF or acetonitrile,preferably DMSO. This reaction is generally allowed to run for about12-24 hours. Appropriate reaction temperatures range from about 70° C.to about 140° C. Approximately 100° C. is preferred.

[0317] The above reaction yields the compound of formula VIII, which canthen be converted into the desired compound having formula IE by thefollowing procedure. First, the compound of formula VIII is reduced byreaction with hydrogen and a palladium or platinum catalyst such aspalladium hydroxide in methanol at a temperature from about 0° C. toabout 70° C., preferably at about room temperature, to form thecorresponding amino derivative. The product of this reaction is thenreacted with an acid chloride of the formula R¹⁰COCl or an acidanhydride of the formula (R¹⁰CO)₂0 wherein R¹⁰ is (C₁-C₆)alkyl, or acompound of the formula R¹⁰C(OC₂H₅)₃, in an appropriate inert solventsuch as decalin, chlorobenzene or xylenes. A mixture of xylenes ispreferred. This reaction is typically conducted at a temperature fromabout 120-150° C., preferably at about 140° C. When R¹⁰COCl is used as areactant, it is preferable to add a stoichiometric amount oftriethylamine (TEA) or another organic tertiary amine base and acatalytic amount of pyridinium p-toluenesulfonic acid or pyridiniump-toluenesulfonate (PPTs) to the reaction mixture. When R¹⁰C(OC₂H₅)₃ isused as a reactant, it is preferable to add a catalytic amount of PPTsto the reaction mixture.

[0318] Removal of the trifluoroacetyl nitrogen protecting group yieldsthe desired compound of the formula IE. This can be accomplished usingmethods well known to those of skill in the art, for example, reactingthe protected compound with a lower alkanol and an aqueous alkali oralkaline earth metal (or ammonium) hydroxide or carbonate, aqueoussodium carbonate, at a temperature from about 50° C. to about 100° C.,preferably at about 70° C., for about two to six hours.

[0319] Scheme 6 illustrates the preparation of compounds of the formulaI wherein R¹ is hydrogen and R² and R³, together with the benzo ring towhich they are attached, form a benzothiazole ring system. Referring toScheme 6, the compound of formula III is reacted with trifluoroaceticanhydride to form the corresponding compound wherein the ring nitrogenis protected by a trifluoroacetyl group, and the resulting nitrogenprotected compound is then reacted with two equivalents oftrifluoromethanesulfonic anhydride and one equivalent of nitric acid toform the corresponding compound of formula IX, wherein there is a singlenitro substituent on the benzo ring. The reaction with trifluoroaceticacid is typically conducted in the presence of pyridine. Both of theabove reactions are typically conducted in a reaction inert solvent suchas a chlorinated hydrocarbon solvent, preferably methylene chloride, ata temperature from about 0° C. to about room temperature, preferably atabout room temperature.

[0320] The above transformation can also be accomplished using othernitration methods known to those skill in the art. Reduction of thenitro group to an amine group can be accomplished as described above toprovide a compound of the formula IX′.

[0321] The compound of formula IX′ is then reacted with a carboxylicacid halide or anhydride of the formula R¹⁰COX or (R¹⁰CO)₂O, wherein Xis halo and R¹⁰ is hydrogen or (C₁-C₆)alkyl, and pyridine, TEA oranother tertiary amine base, to form a compound of the formula X, whichcan then be converted to the desired compound having formula Xi byreacting it with Lawesson's reagent:

[0322] The reaction with R¹⁰COX, wherein X is halo, or (R¹⁰CO)₂O isgenerally carried out at a temperature from about 0° C. to about roomtemperature, preferably at about room temperature. The reaction withLawesson's reagent is generally carried out in a reaction inert solventsuch as benzene or toluene, preferably toluene, at a temperature fromabout room temperature to about the reflux temperature of the reactionmixture, preferably at about the reflux temperature.

[0323] Closure to the benzothiazole ring and nitrogen deprotection toform the desired compound of formula IF can be accomplished by reactingthe compound of formula XI with potassium ferricyanide and sodiumhydroxide in a mixture of water and methanol (NaOH/H₂O/CH₃OH), at atemperature from about 50° C. to about 70° C., preferably at about 60°C. for about 1.5 hours.

[0324] Scheme 7 illustrates a method of preparing the compound offormula III, which is used as the starting material for the process ofScheme 1, or a compound of the formula IG, wherein R² and R³ form a ring(labeled “A” in the Scheme), as defined above in the definition ofcompounds of the formula I. Referring to Scheme 7, the compound offormula XII, wherein X¹ and X² are selected, independently, from chloro,fluoro, bromo and iodo, but where at least one of X¹ and X² is Br- orI-, reacted with cyclopentadiene, in the presence of magnesium metal, ina THF, dioxane or other ethereal solvent, at a temperature from about40° C. to about 100° C., preferably at about the reflux temperature, toform a compound of the formula XIII. Reaction of the resulting compoundof formula XIII with N-methylmorpholine-N-oxide (NMO) and osmiumtetroxide in acetone at about room temperature yields the correspondingcompound of the formula XIIIA.

[0325] The compound having formula XIIIA is then converted into thecorresponding compound of formula XIV using the following procedure.First, the compound of formula XIIIA is reacted with sodium periodate ina mixture of a chlorinated hydrocarbon, preferably dichloroethane (DCE),and water, or with lead tetraacetate in a chlorinated hydrocarbonsolvent, at a temperature from about 0° C. to about room temperature, togenerate a dialdehyde or glycal intermediate. The product of thisreaction is then reacted with benzylamine and sodiumtriacetoxyborohydride in a chlorinated hydrocarbon solvent at atemperature from about 0° C. to about room temperature, preferably atabout room temperature, to form the desired compound of formula XIV.Removal of the benzyl group from the compound of formula XIV yields thecompound of formula III (when ring A is absent) or IG, (when ring A ispresent). This can be accomplished using methods well known to those ofskill in the art, for example, optionally reacting the free base withone equivalent of acid, e.g., hydrochloric acid, (to form thecorresponding acid addition salt), followed by hydrogenolysis andpalladium hydroxide in methanol at about room temperature.

[0326] In the reductive animation step described above and throughoutthis document, alternatives to benzyl amine, such as ammonia,hydroxylamine, alkoxy amines, methyl amine, allyl amine, and substitutedbenzylamines (e.g., diphenylmethyl amine and 2- and 4-alkoxy substitutedbenzyl amines) can also be used. They can be used as free bases, or astheir salts, preferably their acetate salts, and can be subsequentlyremoved by methods described for each in T. W. Greene and G. M. Wuts,Protective Groups in Organic Synthesis (John Wiley & Sons, New York1991).

[0327] The procedure of Scheme 7 can also be used to prepare compoundsof the formula I wherein R² and R³ do not form a ring and are not bothhydrogen, by replacing the starting material of formula XII with theappropriate compound having the formula XII′

[0328] Alternatively, a compound of formula XIII can be converted, viamethods described below and in Scheme 8, to compounds of formula XIV orformula IG or formula III.

[0329] An alternative means of preparing a compound of formula III′, oras appropriate IG′, is illustrated in Scheme 7A. This process can beapplied to produce compounds of compounds of formula I where R¹ ishydrogen, and R² and R³ are as defined above, with the exception of whenR² and R³ are hydroxy, amino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,—C(═O)R¹³, or —(C₁-C6)alkylene-C(═O)R¹³.

[0330] Referring to Scheme 7A, step 1 of is an esterification of acarboxylic acid. A carboxylic acid of formula XXVI is treated with aLewis acid catalyst such as boron trifluoride, or with an acid catalystsuch as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid,methane sulfonic acid, trifluoroacetic acid, or hydrobromic acid,preferably sulfuric acid, in an alcohol solvent such as methanol,ethanol, propanol, butanol, pentanol, or hexanol, preferably methanol,at a temperature between 25 and 120° C., preferably 65 ° C., for aperiod of 30 minutes to 24 hours, preferably 4 hours, to afford acompound of formula XXVIIA.

[0331] Step 2 of Scheme 7A is a cyanohydrin formation. A ketone offormula XXVIIA is treated with a Lewis acid catalyst such as zinciodide, zinc triflate, trimethylsilyl triflate, trimethylsilyl iodide,aluminum chloride, tin (II) chloride, or trimethyl aluminum, preferablyzinc iodide, or with catalytic potassium cyanide and 18-crown-6, andtrimethylsilyl cyanide, in a solvent such as acetonitrile, toluene,methylene chloride, ethyl acetate, isopropyl acetate, methyl-tert-butylether, or tetrahydrofuran, preferably a mixture of acetonitrile andtoluene, at a temperature between 0 and 100° C., preferably at 50° C.,for a period of time between 1 and 24 hours, preferably 5 hours, toafford a compound of formula XXVIIIA.

[0332] Step 3 of Scheme 7A is a hydrogenolysis reaction. A nitrile offormula XXVIIIA is treated with an acid catalyst such asp-toluenesulfonic acid, methane sulfonic acid, hydrochloric acid,sulfuric acid, phosphoric acid, or trifluoroacetic acid, preferablyp-toluenesulfonic acid, and a palladium catalyst such as palladium oncarbon or palladium hydroxide on carbon, preferably palladium hydroxideon carbon, in a solvent such as methanol, ethanol, isopropanol, butanol,propanol, ethyl acetate, isopropyl acetate, or toluene, preferablymethanol, under a hydrogen pressure of 15 to 100 psi, preferably 50 psi,for a time period between 2 and 72 hours, preferably 24 hours, to afforda compound of formula XXIXA.

[0333] Step 4 of Scheme 7A is an amide formation. An amine of formulaXXIXA is treated with a base such as sodium tert-butoxide, sodiummethoxide, sodium ethoxide, sodium hydroxide, potassium tert-butoxide,potassium methoxide, potassium ethoxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, cesium carbonate, sodium hydride,triethylamine, methylimidazole, lutidine, pyridine, methylmorpholine,ethylmorpholine, or diisopropylethylamine, preferably sodiumtert-butoxide, in a solvent such as methanol, ethanol, isopropanol,ethyl acetate, acetonitrile or toluene, preferably methanol, at atemperature between 0 and 120° C., preferably 65 ° C., for a time periodbetween 30 minutes and 72 hours, preferably 2 hours, to afford acompound of formula XXX.

[0334] Step 5 of Scheme 7A is a reduction of an amide. An amide offormula XXX is treated with a reducing agent such as boranetetrahydrofuran complex, diborane, borane dimethylsulfide complex,lithium aluminum hydride, or a combination of sodium borohydride andboron trifluoride, preferably a combination of sodium borohydride andboron trifluoride, in a solvent such as tetrahydrofuran,1,2-dimethoxyethane, 1,2-diethoxyethane, diisopropyl ether, 1,4-dioxane,or methyl-tert-butyl ether, preferably tetrahydrofuran, at a temperaturebetween 0 and 80° C., preferably 50° C., for time period between 1 and24 hours, preferably 5 hours. The product is isolated by crystallizationas a salt of an acid such as p-toluenesulfonic acid, methane sulfonicacid, hydrochloric acid, oxalic acid, citric acid or acetic acid,preferably p-toluenesulfonic acid, in a solvent such as isopropanol,hexane, acetone, ethyl acetate, methyl ethyl ketone, or toluene,preferably isopropanol, to afford the salt form of compound of formulaIG or III.

[0335] Scheme 8, 9 and 10 illustrate methods of preparing compounds ofthe formula I wherein R¹ is hydrogen, and R² and R³ represent a varietyof different substituents, as defined above, but do not form a ring.

[0336] Scheme 8 illustrates a variation of the process shown in Scheme7, which can be used to make a compound identical to that of formulaIlIl except that the benzo ring is substituted with a fluoro group, analkoxy group or any other suitable R² and/or R³ group (R¹⁸ in Scheme 8).This compound is depicted in Scheme 8 as chemical structure 1 H.Referring to Scheme 8, where, for example, R¹⁸ is F, 1,3-difluorobenzeneis reacted with a strong base such as an alkali metal dialkylamine or analkali metal alkyl (or aryl) in an ethereal solvent such as ethyl etheror THF, at a temperature below −50° C., followed by quenching withiodine or N-iodosuccinamide, to form 1,3-difluoro-2-iodobenzene. Thecompound 1,3-difluoro-2-iodobenzene (structural formula XVI in Scheme 8)is then converted into the compound of formula IH by a series ofreactions (represented in Scheme 8 as XVI→XVII→XVIII→XIX→IH) that areanalogous to the series of reactions described above and illustrated inScheme 7 or Scheme 8A for converting compounds of the formula XIII intothose of the formula IG or III. Conversion of the compound of formulaXVI into the compound of formula XVII can also be accomplished bytreating a mixture of the compound of formula XVI and cyclopentadienewith an alkyl lithium reagent, preferably n-butyl lithium, in an inerthydrocarbon solvent such as petroleum ether, toluene or methylcyclohexane, at a temperature from about −20° C. to about roomtemperature, preferably at about 0° C. This procedure is equallyeffective to effect the conversion as set forth in Scheme 7 with orwithout the R¹⁸ group present.

[0337] The compound of formula IH can then be converted into thecorresponding nitrogen protected derivative of formula XX, using themethods described above for synthesizing the compound of formula IV inScheme 1. Nitration of the compound of formula XX using the methoddescribed above for preparing the compound of formula IX in Scheme 6,yields the compound of formula XXI wherein the benzo ring is substitutedwith both a fluoro and nitro group, an alkoxy group and nitro group, oran R¹⁸ substituent and a nitro group. The compound of formula XXI can beused to make a variety of compounds of the formula I wherein one of R²and R³ is fluoro, using methods that are well known to those of skill inthe art, for example, by first converting the nitro group to an aminogroup, converting the amino group to a variety of other substituents, asillustrated in Scheme 10, and then removing the nitrogen protectinggroup.

[0338] The compound of formula XXI acts as a regioisomeric functionalequivalent of the compounds having formulas IIA, VIA and XXII, in thatthe fluorine atom of formula XXI reacts similarly to the nitro and Ygroups of formula IIA, VIA, and XXII, and thus can be subjected to thesame series of reactions as those described above for the latter threecompounds, providing an alternate means for preparing the products ofsuch reactions. Similarly, the alkoxy group of formula XXI (R¹⁸=alkoxy)may be converted into a hydroxyl group before or after introduction ofthe nitro group, and then converted to isomeric products as describedabove. Also, the trifluoromethanesulfonate ester of such hydroxyderivative can act as a Y-group as described.

[0339] Preparation of compounds of formula I where R²=—O(C₁-C₆)alkyl,(C₁-C₆) alkyl or aryl wherein aryl is defined as above in the definitionof formula I and R³ is H or one of the other substituents describedabove in the definition of formula I can be prepared as described aboveand illustrated in Scheme 8 by replacing one of the fluorine atoms ofthe compound of formula XV with —O—(C₁-C₆)alkyl, (C₁-C₆)alkyl or aryl,respectively.

[0340] Scheme 8A illustrates an alternative procedure for obtainingcompounds of formula I where R² and R³ are as defined above, with theexception of (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or nitro (IH′, as depicted).Step 1 of Scheme 8A is an oxidation followed by a reductive amination. Abenzonorbornadiene derivative of formula XVII′ is first treated withozone until the solution develops a blue color between 0° C. and −78 °C., preferably −78° C., in a solvent such as methanol, ordichloromethane, preferably methanol. The ozonide formed is reduced byhydrogenolysis between −78° C. and room temperature, preferably between0° C. and room temperature, with platinum or palladium catalyst such asplatinum oxide, platinum on carbon, palladium on carbon, or palladiumhydroxide on carbon, preferably 5% platinum on carbon, for a period oftime between 5 minutes and 6 hours, preferably 1 hour, under a hydrogenatmosphere between 15 and 100 psi, preferably between 30 and 50 psi.Next, an arylmethylamine, such as benzylamine, 4-methoxybenzylamine, or3,4-dimethoxybenzylamine, preferably benzylamine is added to thereaction mixture at room temperature with an acid catalyst such asformic acid, acetic acid, p-toluenesulfonic acid, oxalic acid, orhydrochloric acid, preferably formic acid, and hydrogenolysis is resumedfor a period of time between 1 and 12 hours, preferably 4 hours, at ahydrogen pressure between 15 and 100 psi, preferably 50 psi, to afford acompound of formula XIX′, where Ar is an aryl group.

[0341] Step 2 of Scheme 8A is a hydrogenolysis reaction. A compound offormula II is treated with an acid such as p-toluenesulfonic acid,hydrochloric acid, sulfuric acid, acetic acid, formic acid, or methanesulfonic acid, preferably p-toluenesulfonic acid, and a palladiumcatalyst such as palladium hydroxide on carbon or palladium on carbon,preferably palladium hydroxide on carbon, in a solvent such as methanol,ethanol, isopropanol, ethyl acetate, or methyl acetate, preferablymethanol, under a hydrogen pressure between 15 and 100 psi, preferably50 psi, at a temperature between room temperature and 60° C., preferably40° C., for a period of time between 1 and 48 hours, preferably 15hours. The product is crystallized as a salt depending on which acidcatalyst is used in a solvent such as isopropanol, hexane, acetone,ethyl acetate, methyl ethyl ketone, or toluene, preferably in a mixtureof isopropanol and hexane, to afford a compound of formula IH′.

[0342] Scheme 9 illustrates methods of preparing compounds of theformula I wherein: (a) R¹ is hydrogen and R² is R⁷R⁸NO₂S—; (b) R¹ and R²are both chloro; and (c) R¹ is hydrogen and R² is R¹³C(═O)—. Thesecompounds are referred to in Scheme 9, respectively, as compounds offormulas IJ, IK and IL.

[0343] Referring to Scheme 9, compounds of the formula IJ can beprepared by reacting the compound of formula IV with two or moreequivalents of a halosulfonic acid, preferably chlorosulfonic acid, at atemperature from about 0° C. to about room temperature. Reaction of thechlorosulfonic acid derivative so formed with an amine having theformula R⁷R⁸NH, wherein R⁷ and R⁸ are defined as above, followed byremoval of the nitrogen protecting group, yields the desired compoundhaving formula IJ.

[0344] Compounds of the formula IK can be prepared by reacting thecompound of formula IV with iodine trichloride in a chlorinatedhydrocarbon solvent, followed by removal of the nitrogen protectinggroup. The reaction with iodine trichloride is typically carried out ata temperature from about 0° C. to about room temperature, and ispreferably carried out at about room temperature. In a similar fashion,the analogous mono- or di-brominated or mono- or di-iodinated compoundscan be prepared by reacting the compound of IV with N-iodosuccinamide orN-bromosuccinimide in a trifluoromethanesulfonic acid solvent, followedby removal of the nitrogen protecting group as described above.

[0345] Reaction of the compound of IV with an acid halide of the formulaR¹³COCl or an acid anhydride of the formula (R¹³CO)₂O, with or without areaction inert solvent such as a chlorinated hydrocarbon solvent,preferably methylene chloride, in the presence of Lewis acid such asaluminum chloride, at a temperature from about 0° C. to about 100° C.,followed by nitrogen deprotection, yields the compound of formula IL.The reaction with the acid halide or anhydride can be carried out usingother known Lewis acids or other Friedel-Crafts acylation methods thatare known in the art.

[0346] The reactions described herein in which —NO₂, —SO₂NR⁷R⁸, —COR¹³,I, Br or Cl are introduced on the compound of formula IV, as depicted inScheme 9 and described above, can be performed on any analogous compoundwherein R² is hydrogen, (C₁-C₆)alkyl, halo, (C₁-C₆)alkoxy or —NHCONR⁷R⁸,producing compounds of the formula I wherein R² and R³ are defined as inthe definition of compounds of the formula I above.

[0347] Compounds that are identical to those of the formula IL, butwhich retain the nitrogen protecting group, can be converted into thecorresponding O-acyl substituted compounds, i.e., those wherein the—C(═O)R¹³ group of formula IL is replaced with a —O—C(═O)R¹³ group,using Baeyer-Villiger processes well known to those skilled in the art.The resulting compounds can be partially hydrolyzed, as described inExample 35, to yield the corresponding hydroxy substituted compounds,and then alkylated to form the corresponding alkoxy substitutedcompounds. Also, as described in Example 36, such O-acyl substitutedcompounds can be used to prepare variably substituted benzisoxazoles.

[0348] Scheme 10 illustrates methods of making compounds of the formulaI wherein: (a) R¹ is hydrogen and R² is chloro; (b) R¹ is hydrogen andR² is cyano; (c) R¹ is hydrogen and R² is amino; and (d) R¹ is hydrogenand R² is R¹³C(═O)N(H)—. These compounds are referred to in Scheme 10,respectively, as compounds of the formula IM, IN, IP and IQ.

[0349] Compounds of formula IM can be prepared from compounds of theformula IX′ by generation of a diazonium salt with, for instance, analkali metal nitrite and strong mineral acid (e.g., hydrochloric acid,sulfuric acid, hydrobromic acid) in water, followed by reaction with acopper halide salt, such as copper (I) chloride. Nitrogen deprotectionby the methods described above yields the desired compound of formulaIM. Alternative methods for the generation of diazonium salts, as knownand practiced by those of skill in the art, can also be used. Theforegoing reaction is generally carried out by temperatures ranging fromabout 0° C. to about 60° C., preferably about 60° C. for about 15minutes to one hour.

[0350] Reaction of the diazodium salt, prepared as described above, withpotassium iodide in an aqueous medium provides the analogous iodidederivative. This reaction is generally carried out at a temperature fromabout 0° C. to about room temperature, preferably at about roomtemperature. The resulting compound, or its analogousN-tert-butylcarbonate protected form, can be used to prepare thecorresponding cyano derivative by reaction with copper (I) cyanide andsodium cyanide in DMF, N,N-dimethylpropylurea (DMPU) or DMSO, preferablyDMF, at a temperature from about 50° C. to about 180° C., preferablyabout 150° C. Nitrogen deprotection as described above provides thedesired compound of formula IM.

[0351] The above described iodide derivative can also be used to accessa variety of other substituents such as aryl, acetylene and vinylsubstituents, as well as the corresponding carbonyl esters and amides,by palladium and nickel catalyzed processes known to those of skill inthe art, such as Heck, Suzuki and Stille couplings and Heckcarbonylations. These compounds and others, wherein R² is halo, alkyl,alkoxy, etc., may be similarly functionalized to generate compoundswherein R² and R³ are as defined above.

[0352] Nitrogen deprotection of the compound of formula IX′ provides thecompound of the formula IP. The compound of formula IX′ can be reactedwith a acyl group having the formula R¹³COCl or (R¹³CO)₂O using themethods described above, followed by nitrogen deprotection to providecompounds of the formula IQ. In a similar fashion, treatment of theprotected amine with a compound having the formula R¹³SO₂X, when X ischloro or bromo, followed by nitrogen deprotection, provides thecorresponding sulfonamide derivative.

[0353] As noted above, suitable amine protecting groups that can beused, alternatively, in the procedures described throughout thisdocument include —COCF₃, —COCCl₃, —COOCH₂CCl₃, —COO(C₁-C₆)alkyl and—COOCH₂C₆H₅. These groups may be removed by methods described for eachin Greene et al.'s Protective Groups in Organic Chemistry, referred toabove. Instances where protecting groups would be modified under thereaction conditions, such as, e.g., a —COOCH₂C₆H₅ group duringnitration, still permit said procedures to operate as described withsaid modified protecting group. Modifying the order of protecting groupincorporation and/or methods of functional group introduction ormodification may also be applied where appropriate.

[0354] In each of the reactions discussed above, or illustrated inSchemes 1-10, above, pressure is not critical unless otherwiseindicated. Pressures from about 0.5 atmospheres to about 5 atmospheresare generally acceptable, with ambient pressure, i.e., about 1atmosphere, being preferred as a matter of convenience.

[0355] The compounds of the formula I and their pharmaceuticallyacceptable salts (hereafter “the active compounds”) can be administeredvia either the oral, transdermal (e.g., through the use of a patch),intranasal, sublingual, rectal, parenteral or topical routes.Transdermal and oral administration are preferred. These compounds are,most desirably, administered in dosages ranging from about 0.01 mg up toabout 1500 mg per day, preferably from about 0.1 to about 300 mg per dayin single or divided doses, although variations will necessarily occurdepending upon the weight and condition of the subject being treated andthe particular route of administration chosen. However, a dosage levelthat is in the range of about 0.001 mg to about 10 mg per kg of bodyweight per day is most desirably employed. Variations may neverthelessoccur depending upon the weight and condition of the persons beingtreated and their individual responses to said medicament, as well as onthe type of pharmaceutical formulation chosen and the time period andinterval during which such administration is carried out. In someinstances, dosage levels below the lower limit of the aforesaid rangemay be more than adequate, while in other cases still larger doses maybe employed without causing any harmful side effects, provided that suchlarger doses are first divided into several small doses foradministration throughout the day.

[0356] The active compounds can be administered alone or in combinationwith pharmaceutically acceptable carriers or diluents by any of theseveral routes previously indicated. More particularly, the activecompounds can be administered in a wide variety of different dosageforms, e.g., they may be combined with various pharmaceuticallyacceptable inert carriers in the form of tablets, capsules, transdermalpatches, lozenges, troches, hard candies, powders, sprays, creams,salves, suppositories, jellies, gels, pastes, lotions, ointments,aqueous suspensions, injectable solutions, elixirs, syrups, and thelike. Such carriers include solid diluents or fillers, sterile aqueousmedia and various non-toxic organic solvents. In addition, oralpharmaceutical compositions can be suitably sweetened and/or flavored.In general, the active compounds are present in such dosage forms atconcentration levels ranging from about 5.0% to about 70% by weight.

[0357] For oral administration, tablets containing various excipientssuch as microcrystalline cellulose, sodium citrate, calcium carbonate,dicalcium phosphate and glycine may be employed along with variousdisintegrants such as starch (preferably corn, potato or tapiocastarch), alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc can be used for tabletting purposes.Solid compositions of a similar type may also be employed as fillers ingelatin capsules; preferred materials in this connection also includelactose or milk sugar, as well as high molecular weight polyethyleneglycols. When aqueous suspensions and/or elixirs are desired for oraladministration the active ingredient may be combined with varioussweetening or flavoring agents, coloring matter and, if so desired,emulsifying and/or suspending agents, together with such diluents aswater, ethanol, propylene glycol, glycerin and various combinationsthereof.

[0358] For parenteral administration, a solution of an active compoundin either sesame or peanut oil or in aqueous propylene glycol can beemployed. The aqueous solutions should be suitably buffered (preferablypH greater than 8), if necessary, and the liquid diluent first renderedisotonic. These aqueous solutions are suitable for intravenous injectionpurposes. The oily solutions are suitable for intraarticular,intramuscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well known to those skilled in theart.

[0359] It is also possible to administer the active compounds topicallyand this can be done by way of creams, a patch, jellies, gels, pastes,ointments and the like, in accordance with standard pharmaceuticalpractice.

Biological Assay

[0360] The effectiveness of the active compounds in suppressing nicotinebinding to specific receptor sites is determined by the followingprocedure which is a modification of the methods of Lippiello, P. M. andFernandes, K. G. (in The Binding of L-[³ H]Nicotine To A Single Class ofHigh-Affinity Sites in Rat Brain Membranes, Molecular Pharm., 29,448-54, (1986)) and Anderson, D. J. and Arneric, S. P. (in NicotinicReceptor Binding of ³ H-Cystisine. ³ H-Nicotine and ³H-Methylcarmbamylcholine In Rat Brain, European J. Pharm., 253, 261-67(1994)).

Procedure

[0361] Male Sprague-Dawley rats (200-300 g) from Charles River werehoused in groups in hanging stainless steel wire cages and weremaintained on a 12 hour light/dark cycle (7 a.m.-7 p.m. light period).They received standard Purina Rat Chow and water ad libitum.

[0362] The rats were killed by decapitation. Brains were removedimmediately following decapitation. Membranes were prepared from braintissue according to the methods of Lippiello and Fernandez (MolecPharmacol, 29, 448-454, (1986) with some modifications. Whole brainswere removed, rinsed with ice-cold buffer, and homogenized at 0° in 10volumes of buffer (w/v) using a Brinkmann Polytron™, setting 6, for 30seconds. The buffer consisted of 50 mM Tris HCl at a pH of 7.5 at roomtemperature. The homogenate was sedimented by centrifugation (10minutes; 50,000×g; 0 to 4° C. The supematant was poured off and themembranes were gently resuspended with the Polytron and centrifugedagain (10 minutes; 50,000×g; 0 to 4° C. After the second centrifugation,the membranes were resuspended in assay buffer at a concentration of 1.0g/100 mL. The composition of the standard assay buffer was 50 mM TrisHCl, 120 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 2 mM CaCl₂ and has a pH of 7.4at room temperature.

[0363] Routine assays were performed in borosilicate glass test tubes.The assay mixture typically consisted of 0.9 mg of membrane protein in afinal incubation volume of 1.0 mL. Three sets of tubes were preparedwherein the tubes in each set contained 50 μL of vehicle, blank, or testcompound solution, respectively. To each tube was added 200 μL of[³H]-nicotine in assay buffer followed by 750 μL of the membranesuspension. The final concentration of nicotine in each tube was 0.9 nM.The final concentration of cytisine in the blank was 1 μM. The vehicleconsisted of deionized water containing 30 μL of 1 N acetic acid per 50mL of water. The test compounds and cytisine were dissolved in vehicle.Assays were initiated by vortexing after addition of the membranesuspension to the tube. The samples were incubated at 0 to 4° C. in aniced shaking water bath. Incubations were terminated by rapid filtrationunder vacuum through Whatman GF/B™ glass fiber filters using a Brandel™multi-manifold tissue harvester. Following the initial filtration of theassay mixture, filters were washed two times with ice-cold assay buffer(5 m each). The filters were then placed in counting vials and mixedvigorously with 20 ml of Ready Safe™ (Beckman) before quantification ofradioactivity. Samples were counted in a LKB Wallach Rackbeta™ liquidscintillation counter at 40-50% efficiency. All determinations were intriplicate.

Calculations

[0364] Specific binding (C) to the membrane is the difference betweentotal binding in the samples containing vehicle only and membrane (A)and non-specific binding in the samples containing the membrane andcytisine (B), i.e.,

[0365] Specific binding=(C)=(A)−(B).

[0366] Specific binding in the presence of the test compound (E) is thedifference between the total binding in the presence of the testcompound (D) and non-specific binding (B), i.e., (E)=(D)−(B).

[0367] % Inhibition=(1−((E)/(C)) times 100.

[0368] The compounds of the invention that were tested in the aboveassay exhibited IC₅₀ values of less than 10 μM.

[0369] The following experimental examples illustrate, but do not limitthe scope of, this invention.

EXAMPLE 1 10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENE

[0370] A) 1,4-Dihydro-1,4-methano-naphthalene

[0371] (Based wholly or in part on a) Wittig, G.; Knauss, E. Chem. Ber.1958, 91, 895. b) Muir, D. J.; Stothers, J. B. Can. J. Chem. 1993, 71,1290.)

[0372] Magnesium turnings (36.5 g, 1.5 M) were stirred in anhydrous THF(250 mL) in a dried 2 L 3 neck round bottom flask equipped with a 250 mLnon-equalizing addition funnel with a nitrogen (N₂) flow adapter,mechanical stirrer and efficient condenser equipped with a N₂ flowadapter. The flask was stirred and warmed to reflux by a removableheating mantle. 2-Fluorobromobenzene (2 g) was added followed by 1 mL of3N ethylmagnesium bromide (EtMgBr in THF). The addition funnel wascharged with a mixture of cyclopentadiene (94.4 g, 1.43 M, Prepared bythe method described in: Org. Syn. Col., Vol. V, 414-418) andbromofluorobenzene (250 g, 1.43 M) which was maintained at 0° C. in aseparate flask by an ice bath, and transferred to the addition funnelvia cannula. Small portions (˜1 mL) of the intimate mixture wereintroduced to assist initiation (˜4 times). After ˜15 minutes, thereaction initiated (exothermic, vapor condensation), the heating mantlewas removed and the contents of the addition funnel was added dropwiseat such rate as to maintain reflux (1.5 hours). The heating mantle wasre-applied and a reflux maintained for 1.5 hours. (TLC 100% hexanesR_(f) 0.67).

[0373] The reaction was cooled to room temperature and quenched with H₂O(500 mL) and carefully with 1N HCl (200 mL, produces H₂ evolution fromunconsumed Mg). To this ˜50 mL concentrated HCl was added to dissolvesolids. Total addition/quench time ˜1 hour. Saturated aqueous sodiumchloride (NaCl) solution (300 mL) was added and product hexanesextracted until no potassium permanganate (KMnO₄) active product isremoved. (4×˜250 mL). The combined organic layer was washed withsaturated NaHCO₃ solution (250 mL), sodium bicarbonate Na₂SO₄ dried andconcentrated to an oil (˜200 g). The product was distilled at 78-83° C.at 15mm (131 g, 64%). (An alternative work-up is described on p.419Fieser and Fieser, Vol. I, Reagents for Organic Synthesis, Wiley, NewYork, N.Y.; 1967).

[0374] B) 1,2,3,4-Tetrahydro-1,4-methano-naphthalene-2,3-diol

[0375] (Except for the work-up method and the quantity of OSO₄ used,based on VanRheenen, V.; Cha, D. Y.; Hartley, W. M. Org. Syn. 1988, 6,342.)

[0376] In a 2 L 3 neck round bottom flask equipped with a N₂ flowadapter, mechanical stirrer was placed1,4-dihydro-1,4-methano-naphthalene (79.5 g, 560 mmol) stirred inacetone (800 mL) and H₂O (100 mL) and N-methyl morpholine N-oxide (67.5g, 576 mmol). To this was added osmium tetroxide (OsO₄) (15 mL of a15mol % t-butyl alcohol solution, 1.48 mmol, 0.26mol %) and the mixturewas stirred vigorously. After 60 hours, the reaction was filtered, andthe white product rinsed with acetone and air dried (60.9 g). The motherliquor was concentrated to an oily solid: acetone trituration,filtration and acetone rinse provided (27.4 g, total 88.3 g, 89%). (TLC50% ethyl acetate/hexanes R_(f) ˜0.5). M.p. 176-177.5 ° C.

[0377] C) 10-Benzyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

[0378] (Based on Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849; andMazzocchi, P. H.; Stahly, B. C. J. Med. Chem. 1979, 22, 455.)

[0379] 1,2,3,4-Tetrahydro-1,4-methano-naphthalene-2,3-diol (40 g, 227.3mmol) was stirred in H₂O (1050 mL) and 1,2-dichloroethane (DCE) (420 mL)in a 2 L round bottom flask under nitrogen with cool water bath (10 °C.). To this sodium periodate (NalO₄) (51 g, 239 mmol) andtriethylbenzyl ammonium chloride (Et₃BnNCl) (50 mg) were added. Theresulting mixture was stirred for 1 hour (slight initial exotherm), thenthe layers were separated and the aqueous layer was extracted with DCE(200 mL). The organic layer was washed with H₂O (4×200 mL, or until noreaction to starch iodide is observed in the aqueous wash) then driedthrough a cotton plug. To this was added benzyl amine (25.5 g, 238.6mmol) and the mixture was stirred for 2 minutes then immediatelytransferred into the sodium triacetoxyborohydride NaHB(OAc)₃/DCE (seebelow) over 10 minutes.

[0380] In a separate 2 L round-bottomed flask under nitrogen wasmagnetically stirred NaHB(OAc)₃ (154 g, 0.727 mmol) in DCE (800 mL) at0° C. (ice bath). To this was added the above mixture over 10 minutes,without delay after the dialdehyde and amine were mixed. The resultingorange mixture was allowed to warm to room temperature and stirred for30-60 minutes.

[0381] The reaction was quenched by addition of saturated sodiumcarbonate (Na₂CO₃) solution (˜300 mL) carefully at first and the mixturewas stirred for 1 hour (pH 9). The layers were separated and the aqueouslayer was extracted with CH₂Cl₂ (2×300 mL). The organic layer was washedwith saturated aqueous NaCl solution (200 mL), dried through a cottonplug, then evaporated to a red oil. This was dissolved in a minimum ofEt₂O and filtered through a Silica pad (3×4 inch) eluting with 15% ethylacetate (ethyl acetate)/hexanes +1% of 37% aqueous ammonium hydroxide(NH₄OH) solution to remove baseline red color. Concentration affords alight yellow oil (48.5 g, 194.8 mmol, 85.7%). (TLC 10% ethylacetate/hexanes R_(f) 0.75). ¹H NMR (400 MHz, CDCl₃) δ7.16 (m, 7H), 6.89(m, 2H), 3.48 (m, 2H), 3.08 (m, 2H), 2.80 (d, J=9.5 Hz, 2H), 2.42 (d,J=9.5 Hz, 2H), 2.27 (m, 1H), 1.67 (d, J=10.0 Hz, 1H). APCl MS m/e 250.3[(M+1)⁺].

[0382] D) 10-Aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

[0383] (For an alternative synthesis, see; Mazzocchi, P. H.; Stahly, B.C. J. Med. Chem. 1979, 22, 455.)

[0384] 10-Benzyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene(70.65 g, 284 mmol) was stirred in ethyl acetate (250 mL) and treatedwith 3N HCl ethyl acetate (1.03 eq.) slowly with cooling (ice bath). Theresulting precipitate was filtered and rinsed with ethyl acetate. Thesolids were dissolved in methanol (250 mL) in a Parr bottle. To this wasadded Pd(OH)₂ (7 g of 20%wt/C) and the mixture was shaken under 50-40psi of H₂ for 24 hours or until done by TLC. The reaction was filteredthrough a Celite pad and concentrated to an oily solid. This wasazeotroped with methanol (methanol) (3 times) then triturated withacetone, treated with ethyl ether (Et₂O) to precipitate product andfiltered. Concentration of the mother liquors and a second treatmentprovided an off white solid (48.95 g, 251 mmol, 88%). (TLC 10%methanol/CH₂Cl₂ (NH₃) R_(f) 0.2). ¹H NMR (400 MHz, CDCl₃) δ7.18 (m, 4H),2.97 (m, 4H), 2.68 (d, J=12.5 Hz, 2H), 2.41 (m, 1H), 1.95 (d, J=11.0 Hz,1H). APCl MS m/e 160.2 [(M+1)⁺].

EXAMPLE 2 4-FLUORO-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

[0385] A) 6-Fluoro-1,4-dihydro-1,4-methano-naphthalene

[0386] (Eisch, J. J.; Burlinson, N. E. J. Amer. Chem. Soc. 1976, 98,753-761. Paquette, L. A.; Cottrell, D. M.; Snow, R. A. J. Amer. Chem.Soc. 1977, 99, 3723-3733.)

[0387] Magnesium turnings (0.66 g, 27.2 mmol) were stirred in anhydrousTHF (10 mL) in a flame dried 75 mL 3 neck round bottom flask equippedwith a non-equalizing addition funnel with a N₂ flow adapter, magneticstirrer and efficient condenser equipped with a N₂ flow adapter. Theflask was stirred and warmed to reflux by a removable heating mantle.2,5-Difluorobromobenzene (0.1 g) was added followed by of 3N EtMgBr inTHF (0.1 mL). The addition funnel was charged with an intimate mixtureof cyclopentadiene (1.71 g, 25.9 mmol) and 2,5-difluorobromobenzene (5.0g, 25.9 mmol). Small portions (0.2 mL) of the intimate mixture wereintroduced to assist initiation (˜4 times). After 15 minutes, thereaction initiated (exotherm, and vapor condensation) and heating wasmaintained as necessary during the addition of the contents of theaddition funnel. The reaction was then maintained at reflux for 1 hour.

[0388] The reaction was cooled to room temperature and quenched with H₂O(20 mL) followed by aqueous 1N HCl solution (20 mL) to dissolve thesolids. Saturated aqueous NaCl solution (30 mL) was added and productwas extracted with hexanes (4×25mL). The combined organic layer waswashed with saturated aqueous NaHCO₃ solution (25 mL), dried (Na₂SO₄),filtered through a Silica plug with hexanes rinse and concentrated to anoil. Chromatography on Silica gel eluting with hexanes provided an oil(780 mg, 19%). (TLC hexanes R_(f) 0.38). ¹H NMR (400 MHz, CDCl₃) δ7.10(m, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.80 (br s, 1H), 6.78 (br s, 1H), 6.59(m, 1H), 3.87 (br s, 2H), 2.32 (d, J=7.0 Hz, 1H), 2.25 (d, J=7.0 Hz,1H).

[0389] B) 6-Fluoro-1,2,3,4-tetrahydro-1,4-methano-naphthalene-2,3-diol

[0390] 6-Fluoro-1,4-dihydro-1,4-methano-naphthalene (680 mg, 4.22 mmol)and N-methyl morpholine N-oxide (599 mg, 4.43 mmol) were stirred inacetone (50 mL) and H₂O (5 mL). To this was added a solution of OsO₄(0.2 mL, 2.5%wt. solution in t-butyl alcohol, 0.02 mmol). After 72hours, Florisil (5 g) and saturated aqueous NaHSO₃ solution (3 mL) wereadded and stirred for 1 hour. The Florisil was filtered and the filtrateconcentrated to produce a crystalline product which was triturated withacetone and filtered (524 mg, 64%). ¹H NMR (400 MHz, CDCl₃) δ7.10 (dd,J=8.0,5.0 Hz, 1H), 6.90 (dd, J=8.0,2.3 Hz, 1H), 6.75 (ddd, J=8.0,8.0,2.3Hz, 1H), 3.79 (s, 2H), 3.18 (d, J =1.5 Hz, 2H), 2.22 (d, J=10.0 Hz, 1H),1.92 (dd, J=10.0,1.5 Hz, 1H). GCMS m/e 194 (M⁺).

[0391] C)10-Benzyl-4-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

[0392] 6-Fluoro-1,2,3,4-tetrahydro-1,4-methano-naphthalene-2,3-diol (524mg, 2.68 mmol) and Et₃NBnCl (10 mg) were vigorously stirred indichloroethane (15 mL) and H₂O (45 mL) then treated with sodiumperiodate (0.603 mg, 2.82 mmol). After 1.5 hours, the layers wereseparated and the aqueous layer extracted with DCE (2×20 mL). Thecombined organic layer was washed with H₂O (4×20 mL) until no reactionto starch iodide paper was observed, then with saturated aqueous NaClsolution (20 mL). The organic layer was dried through a cotton plug andtreated with benzyl amine (0.308 mL, 2.82 mmol) and stirred for 2minutes then transferred to an addition funnel. This solution was addedover ˜10 minutes to a vigorously stirred cooled (0° C.) mixture ofNaHB(OAc)₃ (1.82 g, 8.58 mmol) in DCE (50 mL). After addition wascomplete, the mixture was stirred without cooling for 2 hours. Themixture was quenched with saturated aqueous Na₂CO₃ solution (100 mL) andstirred for 1 hour, then the layers were separated and the aqueous layerwas extracted with CH₂Cl₂ (3×30 mL). The combined organic layer waswashed with saturated aqueous NaCl solution (50 mL), dried through acotton plug and concentrated. Chromatography on Silica gel provided anoil (520 mg, 80%). (TLC 2% acetone/CH₂Cl₂ R_(f) 0.40). ¹H NMR (400 MHz,CDCl₃)δ7.18 (m, 1H), 6.88 (m, 2H), 3.48 (s, 2H), 3.06 (m, 2H), 2.78 (m,2H), 2.41 (m, 2H), 2.27 (m, 1H), 1.69 (d, J=10.5 Hz, 1H).

[0393] D) 4-Fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride

[0394]10-Benzyl-4-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene(390 mg, 1.461 mmol), ammonium formate (3.04 g, 48.2 mmol) and10%Pd(OH)₂/C (30 mg) were combined in methanol (50 mL) and brought toreflux under N₂ for 1.5 hours. Ammonium formate (1.0 g) was added andreflux continued for 0.5 hour. The reaction mixture was filtered througha Celite pad which was rinsed with methanol. The filtrate wasconcentrated. The residues were treated with saturated aqueous Na₂CO₃solution (30 mL) and product extracted with methylene chloride (CH₂Cl₂)(3×25 mL). The organic layer was washed with saturated aqueous NaClsolution (50 mL), dried through a cotton plug and concentrated. Theresidue was treated with 2N HCl methanol (5 mL) and concentrated thentaken up in minimum of methanol and saturated with Et₂O. After stirring18 h, the white crystals were collected by filtration (86 mg, 28%). (TLC5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.27). (data for free base) ¹H NMR (400MHz, CDCl₃) δ7.06 (m, 1H), 6.83 (m, 2H), 2.89 (m, 4H), 2.61 (dd, J=12.0Hz, 2H), 2.37 (m, 1H), 1.87 (d, J=11.5 Hz, 1H). APCl MS m/e 178.2 [(M+1)⁺]. (HCl salt) M.p. 260-262° C.

EXAMPLE 3 4-METHYL-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

[0395] The title compound was prepared by the methods described inExamples 1 and 2 starting with 2-fluoro-5-methylbromobenzene. (data forfree base) ¹H NMR (400 MHz, CDCl₃) δ7.04 (d, J=7.5 Hz, 1H), 6.99 (s,1H), 6.98 (d, J=7.5 Hz, 1H), 2.98-2.90 (m, 4H), 2.63 (m, 2H), 2.35 (m,1H), 2.32 (s, 3H), 1.87 (d, J=11.5 Hz, 1H). APCl MS m/e 174.2 [(M+1)⁺].(HCl salt) M.p. 254-255 ° C. Anal. Calcd. for C₁₂Hl₂F₃N.HCl.⅓H₂O: C,53.44; H, 5.11; N, 5.19. Found C, 53.73; H, 4.82; N, 5.15.

EXAMPLE 44-TRIFLUOROMETHYL-10-AZA-TRICYCLO[6.3.1.0^(2,7)]-DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

[0396] (See Grunewald, G. L.; Paradkar, V. M.; Pazhenchevsky, B.;Pleiss, M. A.; Sall, D. J.; Seibel, W. L.; Reitz, T. J. J. Org. Chem.1983, 48, 2321-2327. Grunewald, G. L.; Markovich, K. M.; Sall, D. J. J.Med. Chem. 1987, 30, 2191-2208.)

[0397] The title compound was prepared by the methods described inExamples 1 and 2 starting with 2-fluoro-5-trifluoromethylbromobenzene.¹H NMR (400 MHz, CD₃OD) δ7.71 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.57 (d,J=8.0 Hz, 1H), 3.46 (m, 4H), 3.21 (d, J=12.5 Hz, 2H), 2.41 (m, 1H), 2.16(d, J=11.5 Hz, 1H). APCl MS m/e 228.2 [(M+1)⁺]. (HCl salt) M.p. 244-246°C. Anal. Calcd. for C₁₂H₁₂F₃N.HCl.⅓H₂O C, 53.44; H, 5.11; N, 5.19. FoundC, 53.77; H, 4.82; N, 5.18.

EXAMPLE 53-TRIFLUOROMETHYL-10-AZA-TRICYCLO[6.3.1.0^(2,7)]-DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

[0398] (See Grunewald, G. L.; Paradkar, V. M.; Pazhenchevsky, B.;Pleiss, M. A.; Sall, D. J.; Seibel, W. L.; Reitz, T. J. J. Org. Chem.1983, 48, 2321-2327. Grunewald, G. L.; Markovich, K. M.; Sall, D. J. J.Med. Chem. 1987, 30, 2191-2208.)

[0399] The title compound was prepared by the methods described inExamples 1 and 2 starting with 2-fluoro-6-trifluoromethylbromobenzene.¹H NMR (400 MHz, CD₃OD) δ7.67-7.50 (3H), 3.65 (br s, 1H), 3.49-3.42 (m,2H), 3.29 (s, 1H), 3.28-3.16 (m, 2H), 2.42 (m, 1H), 2.18 (d, J=11.5 Hz,1H). APCl MS m/e 228.2 [(M+1)⁺]. (HCl salt) M.p. 275-277° C. Anal.Calcd. for C₁₂H₁₂F₃N.HCl.⅓H₂O C, 53.44; H, 5.11; N, 5.19. Found C,53.73; H, 4.83; N, 5.16.

EXAMPLE 6 3-FLUORO-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

[0400] A) 2,6-Difluoroiodobenzene (Roe, A. M.; Burton, R. A.; Willey, G.L.; Baines, M. W.; Rasmussen, A. C. J. Med. Chem. 1968, 11, 814-819.Tamborski, C.; Soloski, E. J. Org. Chem. 1966, 31, 746-749. Grunewald,G. L.; Arrington, H. S.; Bartlett, W. J.; Reitz, T. J.; Sall, D. J. J.Med. Chem. 1986, 29, 1972-1982.) 1,3-Difluorobenzene (57.05 g, 0.5 M) inTHF (75 mL) was added to a −78° C. stirred solution of n-butyllithium(n-BuLi) (200 mL, 2.5 M/hexanes, 0.5 M) and THF (500 mL) under N₂. Bycontrolling the addition rate the internal temperature was maintainedbelow −70° C. The total addition time was ½ hour. The resulting slurrywas stirred an additional ½ hour, then the dispersion was treated with asolution of iodine (126.9 g, 0.5 M) in THF (300 mL) at a rate thatmaintained an internal temperature below −70 ° C. After completeaddition the mixture was allowed to warm to room temperature, and wastreated with H₂O (100 mL) and 10% aqueous Na₂S₂O₃ solution (100 mL) andstirred. The layers were separated and the aqueous layer extracted withhexanes (2×250 mL). The combined organic layer was washed with 10%aqueous Na₂S₂O₃ solution (100 mL), H₂O (100 mL), saturated aqueous NaClsolution (100 mL), dried (Na₂SO₄) filtered and concentrated to give ayellow oil (106.5 g). Distillation at ˜1-5 mm at ˜80° C. provided alight yellow oil (89.5 g, 75%). ¹H NMR (400 MHz, CDC1₃) δ7.30 (m, 1H),6.87 (m, 2H). GCMS m/e 240 (M⁺).

[0401] B) 5-Fluoro-1,4-dihydro-1,4-methano-naphthalene

[0402] A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 mmol) andcyclopentadiene (2.07 g, 31.3 mmol) was stirred at 0° C. in P. ether (70mL, 40-60° C.) under N₂ and treated with n-BuLi (8.74 mL, 2.5M inhexanes, 21.8 mmol) dropwise over 10 minutes. The reaction was quenchedafter 15 minutes by addition of aqueous 1N HCl solution and the productwas extracted with hexanes (3×50 mL). The combined organic layer waswashed with H₂O (50 mL), saturated aqueous NaCl solution (50 mL), dried(MgSO₄), filtered and evaporated. Chromatography on Silica gel providedproduct as an oil (1.5 g, 45%). (TLC hexanes R_(f) 0.55). ¹H NMR (400MHz, CDC1₃) δ7.08 (ddd, J=7.0,1.0,0.8 Hz, 1H), 6.96 (ddd, J=8.5,8.3,7.0Hz, 1H), 6.86 (br s, 2H), 6.72 (ddd, J=8.5,8.3,0.8 Hz, 1H), 4.25 (br s,1H), 3.98 (br s, 1H), 2.36 (ddd, J=7.2,1.7,1.7 Hz, 1H), 2.30 (ddd,J=7.2,1.7,1.5 Hz, 1H). GCMS m/e 160 (M⁺).

[0403] C) 3-Fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride

[0404] The title compound was prepared by the methods described inExamples 2B, C, and D starting with5-fluoro-1,4-dihydro-1,4-methano-naphthalene. ¹H NMR (400 MHz, CD₃OD)δ7.36 (ddd, J=8.3,7.3,5.0 Hz, 1H), 7.21 (d, J=7.3 Hz, 1H), 7.07 (t,J=8.3 Hz, 1H), 3.62 (br s, 1H), 3.42-3.30 (m, 3H), 3.21 (m, 2H), 2.38(m, 1H), 2.12 (d, J=11.5 Hz, 1H). APCl MS m/e 178.4 [(M+1)⁺]. M.p.269-271° C.

EXAMPLE 7 4-NITRO-10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

[0405] A)1-(10-Aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

[0406] 10-Aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride salt (12.4 g, 63.9 mmol) was stirred in CH₂Cl₂ (200 mL).This was cooled (ice bath) and treated with pyridine (12.65 g, 160 mmol)followed by trifluoroacetic anhydride (TFAA) (16.8 g, 11.3 mL, 80 mmol)from an addition funnel over 10 minutes. After ˜3 hours, the solutionwas poured into 0.5N aqueous HCl (200 mL) and the layers separated. Theaqueous layer was extracted with CH₂Cl₂ (3×50 mL) and the combinedorganic layer was washed with 0.5N aqueous HCl (50 mL), H₂O (2×50 mL)and saturated aqueous NaHCO₃ solution (50 mL). This solution was driedthrough a cotton plug, then diluted with ˜3% ethyl acetate and filteredthrough a 2 inch Silica pad eluted with ˜3% ethyl acetate/CH₂Cl₂.Concentration afforded a clear oil which crystallized to give whiteneedles (15.35 g, 60.2 mmol, 94%). (TLC 30% ethyl acetate/hexanes R_(f)0.53). ¹H NMR (400 MHz, CDCl₃) δ7.18 (m, 4H), 4.29 (br d, J=12.6 Hz,1H), 3.84 (br d, J=12.6 Hz, 1H), 3.51 (dd, J=12.6,1.5 Hz, 1H), 3.21 (brs, 1H), 3.10 (br s, 1H), 3.10 (br d, J=12.6 Hz, 1H), 2.37 (m, 1H), 1.92(d, J=10.8 Hz, 1H). GCMS m/e 255 (M⁺). M.p. 67-68° C.

[0407] B)1-(4-Nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

[0408] (Based on the method described by Coon, C. L.; Blucher, W. G.;Hill, M. E. J. Org. Chem. 1973, 25, 4243.) To a solution oftrifluoromethanesulfonic acid (2.4 ml, 13.7 mmol) in CH₂Cl₂ (10 ml)stirred at 0° C. was slowly added nitric acid (0.58 ml, 27.4 mmol)generating a white precipitate. After 10 minutes the resulting mixturewas cooled to −78° C. and treated with1-(10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(3.5 g, 13.7 mmol) in CH₂Cl₂ (15 ml) dropwise from an addition funnelover 5 minutes. The reaction was stirred at −78 ° C. for 30 minutes thenwarmed to 0° C. for 1 hour. The reaction mixture was poured into avigorously stirred ice (100 g). The layers were separated and theaqueous layer extracted with CH₂Cl₂ (3×30 ml). The organic layer wascombined and washed with H₂O (3×30 ml). The combined organic layer waswashed with saturated aqueous NaHCO₃ solution (20 mL) and H₂O (20 mL)then dried through a cotton plug and concentrated to give an orange oilthat solidified on standing (4.2 g). Chromatography yielded pure productas a crystalline solid (3.2 g, 78%). (TLC 30% ethyl acetate/hexanesR_(f) 0.23). ¹H NMR (400 MHz, CDCl₃) δ8.12 (br d, J=8.0 Hz, 1H), 8.08(br s, 1H), 7.37 (br d, J=8.0 Hz, 1H), 4.38 (br d, J=12.6 Hz, 1H), 3.94(br d, J=12.6 Hz, 1H), 3.59 (br d, J=12.6 Hz, 1H), 3.43-3.35 (m, 2H),3.18 (br d, J=12.6 Hz, 1H), 2.48 (m, 1H), 2.07 (d, J=10.8 Hz, 1H). GCMSm/e 300 (M⁺).

[0409] C) 4-Nitro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride

[0410]1-(4-Nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(182 mg, 0.61 mmol) was stirred with Na₂CO₃ (160 mg, 1.21 mmol) inmethanol (3 mL) and H₂O (1 mL) at 70° C. for 18 hours. The mixture wasconcentrated, water was added and the product was extracted with CH₂Cl₂.The organic layer was extracted with 1 N aqueous HCl (3×20 mL) and theacidic layer washed with CH₂Cl₂ (2×20 mL). The aqueous layer wasbasified to pH ˜10 with Na₂CO₃(s) and product was extracted with CH₂Cl₂(3×30 mL). The organic layer was dried through a cotton plug andconcentrated to an oil. This was dissolved in methanol and treated with1 N HCl in methanol, concentrated to solids which were recrystallizedfrom methanol/Et₂O to afford product as a white solid (73 mg, 50%). (TLC5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.38). ¹H NMR (400 MHz, DMSO-d₆) δ8.21(s, 1H), 8.18 (dd, J=8.0,2.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 3.43 (brs, 2H), 3.28 (m, 2H), 3.07 (dd, J=13.0,13.0 Hz, 2H), 2.24 (m, 1H), 2.08(d, J=11.5 Hz, 1H). APCl MS m/e 205.1 [(M+1)⁺] M.p. 265-270° C.

EXAMPLE 8 4-AMINO-10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

[0411] 4-Nitro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene (500mg, 2.08 mmol) was stirred in 1,4-dioxane (40 mL) and treated withsaturated aqueous Na₂CO₃ solution (15 mL). To this was addeddi-t-butyldicarbonate (1.8 g, 8.31 mmol). After stirring 18 hours thereaction was treated with H₂O (50 mL), extracted with CH₂Cl₂ (4×30 mL),dried through a cotton plug and concentrated to provide an oil (500 mg,91%).

[0412] This oil (500 mg, 1.64 mmol) was dissolved in methanol (30 mL),treated with 10%Pd/C (˜50 mg) and hydrogenated under a H₂ atmosphere (45psi) for 1 hour. The mixture was filtered through a Celite pad andconcentrated to a clear oil (397 mg, 88%).

[0413] This oil (50 mg, 0.18 mmol) was stirred in 3N HCl in ethylacetate (3 mL) for 2 hours then concentrated to a white solid (25 mg,56%). ¹H NMR (400 MHz, DMSO-d₆) δ7.38-7.10 (3H), 3.60 (br s, 2H), 3.25(m, 2H), 2.98 (m, 2H), 2.18 (m, 1H), 1.98 (d, J=11.5 Hz, 1H). APCl MSm/e 175.1 [(M+1)⁺] M.p. 189-192° C.

EXAMPLE 9N¹-[10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIEN-4-YL]-ACETAMIDEHYDROCHLORIDE

[0414] A)1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

[0415] Hydrogenation of 1-(4-nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(2.0 g, 6.66 mmol) under a H₂ atmosphere (40 psi) and 10%Pd/C (200 mg)in methanol over 1.5 hours, filtration through Celite and concentrationaffords a yellow oil (1.7 g). (TLC 50% ethyl acetate/hexanes R_(f)0.27). ¹H NMR (400 MHz, CDCl₃) δ6.99 (m, 1H), 6.64 (br s, 1H), 6.57 (m,1H), 4.25 (m, 1H), 3.82 (m, 1H), 3.50 (m, 1H), 3.17-3.07 (m, 3H), 2.35(m, 1H), 1.90 (d, J=10.8 Hz, 1H). GCMS m/e 270 (M⁺).

[0416] B)N-(10-Trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-acetamide

[0417]1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(850 mg, 3.14 mmol) was stirred in CH₂Cl₂ (5 mL) and treated withtriethyl amine (0.53 mL, 3.76 mmol) and acetyl chloride (0.23 mL, 3.2mmol) then stirred 18 hours. Standard NaHCO₃ work-up yielded an oilwhich was chromatographed to provide a clear oil (850 mg, 87%). (50%ethyl acetate/hexanes R_(f) 0.28).

[0418] C)N¹-[10-Azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl]acetamidehydrochloride

[0419]N-(10-Trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-acetamide(100 mg, 0.32 mmol) was stirred with Na₂CO₃ (70 mg, 0.64 mmol) inmethanol (10 mL) and H₂O (2 mL) at 70° C. for 18 hours. The mixture wasconcentrated, water was added and the product was extracted with ethylacetate. The organic layer was extracted with 1N aqueous HCl (3×20 mL)and the acidic layer washed with ethyl acetate (2×20 mL). The aqueouslayer was basified to pH 10 with Na₂CO₃ (s) and product was extractedwith ethyl acetate (3×20 mL). The organic layer was dried (sodiumsulfate (Na₂SO₄)) and concentrated to an oil. This material wasdissolved in methanol and treated with 3N HCl ethyl acetate (3 mL),concentrated and recrystallized from methanol/Et₂O to provide a solid(40 mg, 50%). ¹H NMR (400 MHz, DMSO-d₆) δ9.98 (s, 1H), 9.02 (br m, NH),7.65 (s, 1H), 7.55 (br s, NH), 7.38 (d, J=8.0 Hz,1H), 7.20 (d, J=8.0 Hz,1H), 3.33 (m, 4H), 2.96 (m, 2H), 2.13 (m, 1H), 2.00 (s, 3H), 1.96 (d,J=10.5 Hz, 1H). APCl MS m/e 217.2 [(M+1)⁺]. M.p. 225-230° C.

EXAMPLE 106-METHYL-5-THIA-7,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]PENTADECA-2(10),3,6,8-TETRAENEHYDROCHLORIDE

[0420] A)N-(10-Trifluorothioacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-thioacetamide

[0421]N-(10-Trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-acetamide(850 mg, 2.72 mmol) and2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(Lawesson's reagent) (1.1 g, 2.72 mmol) were combined in toluene (10 mL)and brought to reflux for 1.5 hours. After cooling the reaction wasworked up with ethyl acetate/saturated aqueous NaHCO₃ solution. Theorganic layer was dried (Na₂SO₄), filtered, concentrated andchromatographed on Silica gel to produce product (410 mg, 44%). (50%ethyl acetate/hexanes R_(f) 0.38)

[0422] B)6-Methyl-5-thia-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraenehydrochloride

[0423] The above oil,2,2,2-trifluoro-N-(10-trifluorothioacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-thioacetamide,(360 mg, 1.05 mmol) was dissolved in methanol (10 mL) and 1N NaOH (5 mL)and added to potassium ferricyanide (K₃Fe(CN)₆)(1.72 g, 5.23 mmol) inH₂O (10 mL). This mixture was warmed to 60° C. for 1.5 hours, cooled,concentrated and worked up with ethyl acetate/H₂O. This material wasstirred in dioxane (20 mL) and treated with H₂O (50 mL) and Na₂CO₃ toachieve pH 10. To this was added di-t-butyldicarbonate (436 mg, 2.0mmol) and the mixture was stirred for 18 hours. The reaction wasconcentrated, treated with H₂O and extracted with CH₂Cl₂. The productwas chromatographed (Silica 30% ethyl acetate/hexanes R_(f) 0.41) toyield an oil (100 mg).

[0424] The above product was treated with 3N HCl/ethyl acetate (3 mL)and warmed to reflux for ˜15 minutes then concentrated to a solid whichwas azeotroped with CH₂Cl₂ (two times). These solids were dissolved in aminimum amount of methanol then saturated with Et₂O and stirred. Theresulting white crystalline powder was collected by filtration (40 mg,14%).

[0425]¹H NMR (400 MHz, DMSO-d₆)δ9.46 (s, NH), 7.65 (s, 1H), 7.82 (s,1H), 7.65 (br m, NH), 3.36 (m, 2H), 3.24 (m, 2H), 3.02 (m, 2H), 2.76 (s,3H), 2.23 (m, 1H), 2.06 (d, J=10.8 Hz, 1H). APCl MS m/e 231.1 [(M+1)⁺].M.p. 183-184° C.

EXAMPLE 114,5-DINITRO-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENE

[0426] A)1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

[0427] (Based on the method described in Coon, C. L.; Blucher, W. G.;Hill, M. E. J. Org. Chem. 1973, 25, 4243. For an additional relatedexample of dinitration see: Tanida, H.; Ishitobi, H.; Irie, T.;Tsushima, T. J. Am. Chem. Soc. 1969, 91, 4512.)

[0428] To a solution of trifluoromethanesulfonic acid (79.8 ml, 902.1mmol) in CH₂Cl₂ (550 ml) stirred at 0° C. was slowly added nitric acid(19.1 ml, 450.9 mmol) generating a white precipitate. After 10 minutes,1-(10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(50 g, 196 mmol) in CH₂Cl₂ (300 ml) was added dropwise from an additionfunnel over 30 minutes. The reaction was stirred at 0° C. for 2.5 hoursand then stirred at room temperature for 24 hours. The reaction mixturewas poured into a vigorously stirred mixture of H₂O (500 ml) and ice(400 g). The layers were separated and the aqueous layer back extractedwith CH₂Cl₂ (3×300 ml). The organic layer was combined and washed withH₂O (3×300 ml). The combined aqueous layers were re-extracted withCH₂Cl₂ (2×100 ml). The organic layer was combined and washed withsaturated aqueous NaHCO₃ solution (200 mL) and H₂O (200 mL) then driedthrough a cotton plug and concentrated to solids. Trituration with ethylacetate/hexanes produced off white solids which were filtered and dried(52 g, 151 mmol, 77%. The mother liquor was chromatographed to give anadditional 4.0 g for a total of 56.0 g (82.8%). (TLC 50% ethylacetate/hexanes R_(f) 0.29) ¹H NMR (400 MHz, CDCl₃) δ7.77 (s, 1H), 7.75(s, 1H), 4.39 (br d, J=13.0 Hz, 1H), 3.98 (br d, J=13.0 Hz, 1H), 3.65(d, J=13.0 Hz, 1H), 3.49 (br s, 1H), 3.44 (br s, 1H), 3.24 (br d, J=12.6Hz, 1H), 2.53 (m, 1H), 2.14 (d, J=11.5 Hz, 1H). GCMS m/e 345 (M⁺).

[0429] B)4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

[0430]1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(3.7 g, 10.7 mmol) and Na₂CO₃ (2.3 g, 21.4 mmol) were combined inmethanol (50 mL) and H₂O (20 mL) then warmed to reflux for 18 hours. Thereaction was cooled, concentrated, treated with H₂O and extracted withCH₂Cl₂ (3×50 mL) then dried through a cotton plug. After concentration,the residue was chromatographed to provide brown solids. (1.9 g, 71%).(TLC 5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.36). ¹H NMR (400 MHz, CDCl₃)δ7.69(s, 2H), 3.17 (br s, 2H), 3.11 (d, J=12.6 Hz, 2H), 2.53 (m, 1H), 2.07(d, J=11.0 Hz, 1H). GCMS m/e 249 (M⁺).

EXAMPLE 126-METHYL-7-PROPYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

[0431] A)4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester

[0432] 4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene,(1.9 g, 7.6 mmol) was stirred in 1,4-dioxane (75 mL) and treated withsaturated aqueous Na₂CO₃ solution (10 mL). To this was addeddi-t-butyidicarbonate (3.31 g, 15.2 mmol). After stirring 6 hours thereaction was treated with H₂O ( 50 mL) and extracted with ethyl acetate(4×25 mL), dried (Na₂SO₄), filtered, concentrated and chromatographed toprovide product (1.9 g, 71%). (TLC 30% ethyl acetate/hexanes (NH₃) R_(f)0.58). ¹H NMR (400 MHz, CDCl₃) δ7.77 (br s, 1H), 7.72 (br s, 1H), 4.08(m, 1H), 3.92 (m, 1H), 3.39 (br s, 1H), 3.27 (br s, 1H), 3.25 (m, 1H),3.18 (m, 1H), 2.46 (m, 1H), 2.02 (d, J=11.0 Hz, 1H).

[0433] B)4,5-Diamino-10-aza-tricyclo[6.3.1.0^(2,7)dodeca-2(7).3.5-triene-10-carboxylicacid tert-butyl ester

[0434]4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (1.9 g, 5.44 mmol) was hydrogenated in methanolunder a H₂ atmosphere (45 psi) over 10%Pd/C (100 mg) for 1.5 hours thenfiltered through a Celite pad and concentrated to white solids (1.57 g,100%). (TLC 5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.14).

[0435] C)6-Methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester

[0436] (For conditions, see; Segelstein, B. E.; Chenard, B. L.; Macor,J. E.; Post, R. J. Tetrahedron Lett. 1993, 34, 1897.)

[0437]4,5-Diamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (700 mg, 2.42 mmol) was dissolved in ethanol (10mL) and acetic acid (HOAc) (1 mL) and treated with1-ethoxyethylenemalononitrile (329 mg, 2.42 mmol). The resulting mixturewas warmed to 60° C. and stirred 18 hours. The reaction was cooled,concentrated treated with H₂O and saturated aqueous Na₂CO₃ solution andextracted with ethyl acetate (3×50 mL), then dried (Na₂SO₄). Afterfiltration and concentration, the residue was chromatographed to providebrown solids (247 mg, 36%). (TLC 5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.28).

[0438] D)6-Methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester

[0439] (For conditions, see; Pilarski, B. Liebigs Ann. Chem. 1983,1078.)6-Methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylic acid tert-butyl ester (80 mg, 0.267 mmol) was stirred in50% aqueous NaOH solution (3 mL) and DMSO (1 mL) then treated with1-iodopropane (0.03 mL, 0.321 mmol). This mixture was warmed to 40° C.for 2 hours then cooled, treated with H₂O and extracted with ethylacetate. The organic layer was washed with H₂O (3 times) then dried(Na₂SO₄), filtered and concentrated to an oil (90 mg, 0.253 mmol). (TLC5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.15).

[0440] E)6-Methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraenehydrochloride

[0441]6-Methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester (90 mg, 0.253 mmol) was dissolved in 3N HCl ethylacetate (5 mL) and warmed to 100° C. for ½ hour. The mixture was cooled,concentrated, slurried in ethyl acetate, and filtered to provide a whitesolid (25 mg, 34%). ¹H NMR (400 MHz, DMSO-d₆) δ9.56 (s, NH), 7.91 (s,1H), 7.83 (br m, NH), 7.74 (s, 1H), 4.38 (m, 2H), 3.48 (m, 2H), 3.32 (m,2H), 3.10 (m, 2H), 2.87 (s, 3H), 2.28 (m, 1H), 2.15 (d, J=11.0 Hz, 1H)1.85 (m, 2H), 0.97 (m, 3H). M.p. 147-150° C.

EXAMPLE 135,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

[0442] A)5,7,13-Triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester (For conditions, see; Segelstein, B. E.; Chenard,B. L.; Macor, J. E.; Post, R. J. Tetrahedron Lett. 1993, 34, 1897.)

[0443]4,5-Diamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (1.0 g, 3.45 mmol) was dissolved in ethanol (10mL) and HOAc (1 mL) and treated with ethoxymethylenemalononitrile (421mg, 3.45 mmol). The resulting mixture was warmed to 60° C. and stirred18 hours. The reaction was cooled, concentrated treated with H₂O andsaturated aqueous Na₂CO₃ solution and extracted with ethyl acetate (3×50mL), then dried (Na₂SO₄). After filtration and concentration, theresidue was chromatographed to provide brown solids (580 mg, 56%). (TLC5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.28)

[0444] B)5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraenehydrochloride

[0445]5,7,13-Triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester was converted to the title compound by the methodsdescribed in Example 12E. ¹H NMR (400 MHz, D₂O) δ8.95 (s, 1H), 7.67 (s,2H), 3.45 (brs, 2H), 3.31 (d, J=12.5 Hz, 2H), 3.13 (d, J=12.5Hz, 2H),2.30 (m, 1H), 1.99 (d, J=11.5 Hz, 1H). APCl MS m/e 200.1 [(M+1)⁺].M.p.>250° C.

EXAMPLE 147-METHYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

[0446] Utilizing the methods described in Example 12D,5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester was converted to the title compound by reactionwith iodomethane followed by deprotection as described in Example 12E.¹H NMR (400 MHz, D₂O ) δ8.97 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 3.94(s, 3H), 3.48 (m, 2H), 3.33 (d, J=12.2 Hz, 2H), 3.14 (d, J=12.2 Hz, 2H),2.34 (m, 1H), 2.03 (d, J=11.5 Hz, 1H). APCl MS m/e 214.2 [(M+1)⁺].

EXAMPLE 156-METHYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10)0.^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

[0447]6-Methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester was converted to the title compound by the methodsdescribed in Example 12E. ¹H NMR (400 MHz, DMSO-d₆)δ9.40 (br m, NH),7.77 (br m, NH), 7.70 (s, 1H), 3.44 (m, 2H), 3.30 (m, 2H), 3.05 (br d,J=11.0 Hz, 2H), 2.79 (s, 3H), 2.23 (m, 1H), 2.10 (d, J=10.8 Hz, 1H).GCMS m/e 213.5 (M⁺).

EXAMPLE 166,7-DIMETHYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

[0448] Utilizing the methods described in Example 12D,6-methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester was converted to the title compound by reactionwith iodomethane followed by deprotection as described in Example 12E.¹H NMR (400 MHz, DMSO-d₆) δ9.52 (s, NH), 7.84 (s, 1H), 7.82 (br m, NH),7.72 (s, 1H), 3.90 (s, 3H), 3.45 (m, 2H), 3.28 (m, 2H), 3.04 (m, 2H),2.82 (s, 3H), 2.23 (m, 1H), 2.12 (d, J=11.0 Hz, 1H). APCl MS m/e 228.2[(M+1)⁺]. M.p. 225-230° C.

EXAMPLE 177-PROPYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

[0449] Utilizing the methods described in Example 12D,5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester was converted to the title compound by reactionwith iodopropane followed by deprotection as described in Example 12E.¹H NMR (400 MHz, DMSO-d₆) δ9.52 (s, 1H), 9.45 (br s, NH), 7.97 (s, 1H),7.85 (s, 1H), 7.83 (br m, NH), 4.43 (m, 2H), 3.49 (m, 2H), 3.33 (m, 2H),3.08 (m, 2H), 2.28 (m, 1H), 2.15 (d, J=11.0 Hz, 1H), 1.92 (m, 2H), 0.93(m, 3H). APCl MS m/e 242.2 [(M+1)⁺]. M.p. 170-171° C. (subl.).

EXAMPLE 187-BUTYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

[0450] A)4-Butylamino-5-nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (For conditions, see; Senskey, M. D.; Bradshaw, J.D.; Tessier, C. A.; Youngs, W. J. Tetrahedron Lett. 1995, 36, 6217.)

[0451]4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (500 mg, 1.43 mmol) and 1-butylamine (1.42 mL,14.3 mmol) were combined in THF (5 mL) and stirred 4 hours. The mixturewas diluted with ethyl acetate (50 mL) and washed with H₂O (3×30 mL)then dried (Na₂SO₄), filtered and concentrated to an oil. This oil waspassed through a Silica gel filter column to remove baseline impuritieseluting with 30% ethyl acetate/hexanes (510 mg, 1.41 mmol, 99%).

[0452] B)4-Butylamino-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester

[0453]4-Butylamino-5-nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (460 mg, 1.27 mmol) was treated with ammoniumformate (850 mg, 12.7 mmol) and 10%Pd(OH)₂/C (50 mg) in methanol (20 mL)and brought to reflux for 1 hour then filtered through a Celite pad andconcentrated. The solids were treated with saturated aqueous Na₂CO₃solution, extracted with CH₂Cl₂ (3×30 mL) and dried by filtrationthrough a cotton plug to give an oil (440 mg, 100%).

[0454] C)7-Butyl-5,7,13-triazatetracyclo[9.3.10^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester

[0455]4-Butylamino-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (440 mg, 1.27 mmol) was dissolved in ethanol (20mL) and HOAc (2 mL) and treated with ethoxymethylenemalononitrile (186mg, 1.52 mmol). The resulting mixture was warmed to 60° C. and stirred18 hours. The reaction was cooled, concentrated, treated with H₂O andsaturated aqueous Na₂CO₃ solution then extracted with ethyl acetate(3×50 mL) and dried (Na₂SO₄). After filtration and concentration, theresidue was chromatographed to provide a yellow oil. (400 mg, 89%). (TLC5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.70).

[0456] D)7-Butyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraenehydrochloride

[0457]7-Butyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester was converted to the title compound by the methodsdescribed in Example 12E. ¹H NMR (400 MHz, DMSO-d₆)δ9.93 (brs, NH), 9.68(s, 1H), 7.99 (s, 1H), 7.92 (br m, NH), 7.87 (s, 1H), 4.50 (m, 2H), 3.49(m, 2H), 3.30 (m, 2H), 3.08 (m, 2H), 2.26 (m, 1H), 2.15 (d, J=11.0 Hz,1H), 1.88 (m, 2H), 1.32 (m, 2H), 0.82 (t, J=7.0 Hz, 3H). APCl MS m/e256.2 [(M+1)⁺]. M.p. 204-208° C.

EXAMPLE 197-ISOBUTYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

[0458]4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester and isobutylamine were converted to the titlecompound utilizing the methods described in Example 18A-D. ¹H NMR (400MHz, CDCl₃) δ7.74 (s, 1H), 7.52 (s, 1H), 7.14 (s, 1H), 3.90 (dd,J=7.5,2.0 Hz, 2H), 3.04-2.97 (m, 4H), 2.70 (dd, J=12.8,2.3 Hz, 2H), 2.42(m, 1H), 2.19 (m, 1H), 1.98 (d, J=10.5 Hz, 1H), 0.93 (m, 6H). APCl MSm/e 256.2 [(M+1)⁺]. M.p. 147-150° C. (subl.).

EXAMPLE 206-METHYL-7-ISOBUTYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

[0459] A)6-Methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5.8-tetraene-13-carboxylicacid tert-butyl ester

[0460]4-Amino-5-isobutylamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (250 mg, 0.74 mmol) from Example 19B was dissolvedin ethanol (10 mL) and HOAc (2 mL) and treated with1-ethoxyethylenemalononitrile (118 mg, 0.87 mmol). The reactionproceeded as in Example 18C (18h) and was worked up similarly to provideproduct (TLC 3% methanol/CH₂Cl₂ (NH₃) R_(f) 0.57).

[0461] B)6-Methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraenehydrochloride

[0462]6-Methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester was converted to the title compound by the methodsdescribed in Example 12E. APCl MS m/e 270.3 [(M+1)⁺]. M.p. 129-130° C.(subl.).

EXAMPLE 217-PHENYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

[0463] Utilizing the methods described in Example 18A,4,5-dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester and aniline were converted to4-phenylamino-5-nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl at 75° C. for 4 hours in the coupling step. This wasthen converted to the title compound utilizing the methods described inExample 18B,C,D. ¹H NMR (400 MHz, DMSO-d₆)δ9.08 (1H), 7.78-7.57 (m, 7H),3.47-3.00 (m, 6H), 2.23 (m, 1H), 2.09 (d, J=11.5 Hz, 1H). APCl MS m/e276.2 [(M+1)⁺]. M.p. 210-213° C.

EXAMPLE 226-METHYL-7-PHENYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

[0464] Utilizing the methods described in Example 21 and Example 20,4,5-dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester and aniline were converted to the title compound.¹H NMR (400 MHz, DMSO-d6) δ7.79 (s, 1H), 7.73-7.56 (m, 5H), 7.32 (s,1H), 3.46-2.99 (m, 6H), 2.66 (s, 3H), 2.23 (m, 1H), 2.08 (d, J=11.0 Hz,1H). APCl MS m/e 290.2 [(M+1)⁺]. M.p.>250° C.

EXAMPLE 237-NEOPENTYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

[0465] Utilizing the methods described in Example 18A-D,4,5-dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester and neopentylamine were converted to the titlecompound. t-Boc precursor GCMS m/e 369 (M⁺). (HCl salt) M.p.>250° C.

EXAMPLE 246-METHYL-7-NEOPENTYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

[0466] Utilizing the methods described in Examples 21 and 20,4,5-dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester and neopentylamine were converted to the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ7.31 (s ,1H), 7.27 (s ,1H), 7.02(br s, , NH), 4.41 (t, J=13.0 Hz, 2H), 3.90 (s, 3H), 3.47-3.26 (m, 6H),2.20 (m, 1H), 2.00 (d, J=11.5 Hz, 1H), 0.90 (s, 9H). t-Boc precursorAPCl MS m/e 384.2 [(M+1)⁺]. M.p.>250° C.

EXAMPLE 256,7-DIMETHYL-5,8,14-TRIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]-HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE

[0467] (Based on the following procedure: Jones, R. G.; McLaughlin, K.C. Org. Syn. 1963, 4, 824. b) Ehrlich, J., Bobert, M. T. J. Org. Chem.1947, 522.)

[0468]4,5-Diamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (100 mg, 0.35 mmol) was warmed to 80° C. in H₂O (5mL). To this butane 2,3-dione (0.034 mL, 0.38 mmol) was added under N₂for 2 hours. The reaction was cooled to room temperature and extractedwith ethyl acetate (3×40 ml). The combined organic layer was washed withH₂O (2×30 ml), dried (Na₂SO₄), filtered, concentrated andchromatographed on Silica gel to provide an oil (120 mg, 100%). The oilwas dissolved in 2N HCl methanol (5 mL) and warmed to reflux for 30minutes, then concentrated. Recrystallization from methanol/Et₂Oprovided a white powder (50 mg, 43%). (TLC ethyl acetate R_(f) 0.14). ¹HNMR (400 MHz, DMSO-d₆) δ7.85 (s, 2H), 3.50 (br s, 2H), 3.32 (d, J=12.5Hz, 2H), 3.10 (d, J=12.5 Hz, 2H), 2.64 (s, 6H), 2.24 (m, 1H), 2.13 (d,J=11.0 Hz, 1H). t-Boc precursor APCl MS m/e 340.3 [(M+1)^(+].)

EXAMPLE 265,8,14-TRIAZATETRACYCLOr10.3.1.0^(2,11).0^(4,9)]-HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE

[0469] A)1-(4,5-Diamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

[0470] 1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(3.0 g, 8.70 mmol) was hydrogenated in methanol (30 ml) under H₂ (45psi) over Pd(OH)₂ (300 mg of 20 wt%/C, 10%wt). After 2.5 hours thereaction was filtered through a Celite pad and rinsed with methanol (30ml). The solution was concentrated to a light brown oil whichcrystallized (2.42 g, 96%). (TLC 10% methanol/CH₂Cl₂ R_(f) 0.56). APClMS m/e 286.2 [(M+1 )⁺]. M.p. 129-131° C.

[0471] B)1-(5,8,14-Triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene)-2,2,2-trifluoro-ethanone

[0472]1-(4,5-Diamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(500 mg, 1.75 mmol) was stirred in THF (2 ml). This mixture was treatedwith H₂O (2 mL) and glyoxal sodium bisulfite addition compound hydrate(931 mg, 3.50 mmol) then stirred at 55° C. for 2.5 hours. The reactionwas cooled to room temperature and extracted with ethyl acetate (3×40ml). The combined organic layer was washed with H₂O (2×30 ml), dried(Na₂SO₄), filtered, concentrated and chromatographed on Silica gel toprovide an off white powder (329 mg, 60%). (TLC 25% ethylacetate/hexanes R_(f) 0.40). M.p. 164-166° C.

[0473] C)5,8,14-Triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-Pentaenehydrochloride

[0474]1-(5,8,14-Triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene)-2,2,2-trifluoro-ethanone(320 mg, 1.04 mmol) was slurried in methanol (2.0 ml) and treated withNa₂CO₃ (221 mg, 2.08 mmol) in H₂O (2.0 ml). The mixture was warmed to70° C. for 2 hours, then concentrated, treated with H₂O (20 mL) andextracted with CH₂Cl₂ (3×10 ml). The organic layer was dried through acotton plug and concentrated to give a light yellow oil (183 mg, 83%)which solidified upon standing (M.p. 138-140° C.). This material wasdissolved in methanol (10 mL), treated with 3M HCl/ethyl acetate (3 ml),concentrated and azeotroped with methanol (2×20 mL) to give solids whichwere recrystallized from methanol/Et₂O to afford product as a whitesolid (208 mg, 97%). (TLC 5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.26). ¹H NMR(400 MHz, CD₃OD) δ8.94 (s, 2H), 8.12 (s, 2H), 3.70 (m, 2H), 3.54 (d,J=12.5 Hz, 2H), 3.35 (d, J=12.5 Hz, 2H), 2.49 (m, 1H), 2.08 (d, J=11.0Hz, 1H). GCMS m/e 211 (M⁺). M.p. 225-230° C.

EXAMPLE 2714-METHYL-5,8,14-TRIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]-HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE

[0475]5,8,14-Triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene(207 mg, 0.98 mmol) was treated with 37% aqueous formaline solution (1mL) and formic acid (1 mL) then warmed to 80° C. for 1 hour. Thereaction was poured into water, made basic (NaOH, pH ˜11) and extractedwith ethyl acetate. The organic layer was dried (Na₂SO₄), concentratedand chromatographed on Silica gel to provide a yellow solid. This wasstirred in methanol (2 mL) and treated with 3N HCl ethyl acetate (2 mL).After concentration the solids were recrystallized from methanol/Et₂O toafford product as a white solid (70 mg, 27%). (2% methanol/CH₂Cl₂ (NH₃)R_(f) 0.47). ¹H NMR (400 MHz, CDCl₃) δ8.71 (s, 2H), 7.80 (s, 2H), 3.37(br s, 2H), 3.03 (m, 2H), 2.47 (m, 2H), 2.32 (m, 1H), 2.18 (br s, 3H),1.84 (d, J=11.0 Hz, 1H). APCl MS m/e 226.2 [(M+1)⁺]. M.p.>250° C.

EXAMPLE 285-OXA-7,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,6,8-TETRAENEHYDROCHLORIDE

[0476] A)2,2,2-Trifluoro-1-(4-hydroxy-5-nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone

[0477]1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(900 mg, 2.61 mmol) and potassium acetate (KOAc) (2.6 g, 26.1 mmol) weredissolved in DMSO (10 mL) and warmed with stirring to 100° C. for 16hours. The mixture was cooled and diluted with H₂O (50 mL) thenextracted with 80% ethyl acetate/hexanes (6×25 mL). The organic layerwas washed with H₂O (3×20 mL), dried (Na₂SO₄), filtered and concentratedand purified by chromatography to give an oil (575 mg, 70%). (TLC 50%ethyl acetate/hexanes (NH₃) R_(f) 0.56)

[0478] B)2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)dodeca-2(7),3,5-trien-10-yl)-ethanone

[0479]2,2,2-Trifluoro-1-(4-hydroxy-5-nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone(575 mg, 1.82 mmol) was hydrogenated in methanol under a H₂ atmosphereat (45 psi) over 10%Pd/C (80 mg) for 1.5 hours then filtered through aCelite pad and concentrated to white solids (450 mg, 86%). (TLC 5%methanol/CH₂Cl₂ (NH₃) R_(f) 0.6). ¹H NMR (400 MHz, CD₃OD) δ6.67-6.59 (m,2H), 4.12 (m, 1H), 3.73 (m, 1H), 3.73 (m, 1H), 3.51 (m, 1H), 3.07 (m,2H), 2.24 (m, 1H), 1.94 (d, J=10.5 Hz, 1H). GCMS m/e 286 (M⁺).

[0480] C)2,2,2-Trifluoro-1-(5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene)-ethanone(Goldstein, S. W.; Dambek, P. J. J. Het Chem. 1990, 27, 335.)

[0481]2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone(150 mg, 0.524 mmol), trimethyl orthoformate (0.19 mL, 1.73 mmol),pyridinium-p-toluenesulfonic acid (PPTS, 18 mg, 0.07 mmol) and xylenes(10 mL) were combined under nitrogen and stirred at 135° C. for 18hours. The mixture was cooled, treated with H₂O and extracted with ethylacetate. The extracts were dried (Na₂SO₄), filtered, concentrated andpurified by chromatography to give an oil (110 mg, 71 %). (TLC 20% ethylacetate/hexanes R_(f) 0.40)

[0482] D)5-Oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraenehydrochloride

[0483]2,2,2-Trifluoro-1-(5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene)-ethanone(110 mg, 0.37 mmol) was stirred in methanol (5 mL) and treated withNa₂CO₃ (78 mg, 0.74 mmol) in H₂O (2 mL). The stirred mixture was warmedto 80° C. for 2 hours, concentrated to solids, diluted with H₂O andextracted with ethyl acetate (3×40 mL). The product was extracted intoaqueous 1N HCl solution (2×40 mL) which was washed with ethyl acetatethen neutralized with saturated aqueous Na₂CO₃ solution to pH˜10. Theproduct was extracted with ethyl acetate (3×40 mL), dried (Na₂SO₄),concentrated and chromatographed on Silica gel to produce an oil. (TLC5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.19).

[0484] The oil was dissolved in methanol and treated with 3N HCl ethylacetate (4 mL) then concentrated, stirred in a minimum of CH₂Cl₂ andsaturated with hexanes. After 18 hours, the product was collected byfiltration (55 mg, 63%). ¹H NMR (400 MHz, CD₃OD) δ8.47 (s, 1H), 7.70 (s,1H), 7.65 (s, 1H), 3.41 (m, 2H), 3.30 (m, 2H), 3.10 (d, J=12.5 Hz, 2H),2.47 (m, 1H), 2.15 (d, J=11.0 Hz, 1H). APCl MS m/e 201.03 [(M+1)⁺].

EXAMPLE 296-METHYL-5-OXA-7,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,6,8-TETRAENEHYDROCHLORIDE

[0485] A) 2,2,2-Trifluoro-1-(6-methyl5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene)-ethanone

[0486]2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone(150 mg, 0.524 mmol), triethyl orthoacetate (0.34 mL, 1.83 mmol),pyridinium-p-toluenesulfonic acid (PPTS, 20 mg, 0.08 mmol) and xylenes(10 mL) were combined under nitrogen and stirred at 135° C. for 18hours. Work-up, isolation and purification as in Example 28C providedthe title compound (90 mg, 55%).

[0487] B)6-Methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraenehydrochloride

[0488] 2,2,2-Trifluoro-1-(6-methyl5-oxa-7,13-diazatetracyclo[9.3.1.0^(2.10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene)-ethanone(90 mg, 0.30 mmol) was stirred in methanol (5 mL) and treated withNa₂CO₃ (61 mg, 0.58 mmol) in H₂O (2 mL). The stirred mixture was warmedto 80° C. for 2 hours, concentrated to solids, diluted with H₂O andextracted with ethyl acetate (3×40 mL). The solution was dried (Na₂SO₄),concentrated, and chromatographed on Silica gel to produce an oil. (TLC10% methanol/CH₂Cl₂ (NH₃) R_(f) 0.18). ¹H NMR (free base) (400 MHz,CDCl₃) δ7.40 (s, 1H), 7.26 (s, 1H), 3.05-2.98 (m, 4H), 2.72 (d, J=12.8Hz, 2H), 2.59 (s, 3H), 2.46 (m, 1H), 1.98 (d, J=10.5 Hz, 1H).

[0489] The oil was dissolved in methanol and treated with 3N HCl ethylacetate (4 mL) then concentrated, stirred in a minimum of CH₂Cl₂ andsaturated with hexanes. After 18 hours, the product was collected byfiltration (10 mg, 13%). APCl MS m/e 215.2 [(M+1)⁺]. M.p.>250° C.

EXAMPLE 302-FLUORO-N-(4-HYDROXY-10-AZA-TRICYCLO[6.3.1.0^(2,7)]-DODECA-2(7),3,5-TRIEN-5-YL)-BENZAMIDEHYDROCHLORIDE

[0490]2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone(150 mg, 0.524 mmol), 2-fluorobenzoyl chloride (0.07 mL, 0.576 mmol),pyridinium-p-toluenesulfonic acid (PPTS, 20 mg, 0.08 mmol), pyridine(0.046 mL, 0.576 mmol) and xylenes (5 mL) were combined under nitrogenand stirred at 135° C. for 18 hours. After 24 hours, additional PPTS (50mg) was added and the material stirred at 135° C. for an additional 24hours. Work-up as above provided crude product (145 mg, 0.375 mmol)which was combined with Na₂CO₃(s) (80 mg, 0.75 mmol) in methanol (5 mL)and H₂O (2 mL) and heated to reflux. After 3 hours, the reaction wascooled and diluted with water then extracted with CH₂Cl₂ (4×40 mL),dried through a cotton plug then chromatographed to remove baselineimpurity (5% methanol/CH₂Cl₂ (NH₃)). The crude material was treated withexcess 3N HCl ethyl acetate and concentrated, then dissolved in aminimum of methanol and the solution was saturated with Et₂O andstirred. After stirring 4 hours the product was collected by filtration(85 mg, 68%). ¹H NMR (400 MHz, CD₃OD)δ7.99 (m, 2H), 7.59 (m, 1H),7.36-7.23 (m, 2H), 6.82 (s, 1H), 2.99 (m, 4H), 2.78 (m, 2H), 2.35 (m,1H), 1.96 (d, J=10.5 Hz, 1H). APCl MS m/e 313.1 [(M+1)⁺]. M.p. 125-130°C. (subl.).

EXAMPLE 31 4-CHLORO-10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

[0491] A)1-(4-Chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

[0492] Copper(l)chloride (CuCl) was prepared as follows: CuSO₄ (4.3 g)and NaCl (1.2 g) were dissolved in hot H₂O (14 mL). sodium bisulfite(NaHSO₃) (1 g) and sodium hydroxide (NaOH) (690 mg) were dissolved inH₂O (7 mL) and added to the hot acidic solution over 5 minutes. Theprecipitated white solids were filtered and washed with water.

[0493]1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(460 mg, 1.7 mmol) was dissolved in H₂O (2 mL) and concentrated HClsolution (1 mL) then cooled to 0° C. and treated with a solution ofsodium nitrite (NaNO₂) (275 mg) in H₂O (1 mL) dropwise. To the resultingsolution was added a CuCl (202 mg, prepared as described above, 2.04mmol) in concentrated HCl solution (2 mL) over 10 minutes (gas evolutionobserved). The resulting solution was warmed to 60° C. for 15 minutes,then was cooled to room temperature and extracted with ethyl acetate(4×30 mL). After drying over Na₂SO₄, the solution was filtered andconcentrated to an oil which was filtered through a Silica pad to removebaseline material eluting with 50% ethyl acetate/hexanes to give an oil(470 mg, 95%).

[0494] B) 4-Chloro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride1-(4-Chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(470 mg, 1.62 mmol) and Na₂CO₃ (344 mg, 3.24 mmol) in methanol (30 mL)and H₂O (10 mL) were heated to reflux. After 2 hours, the reaction wascooled and diluted with water then extracted with ethyl acetate (4×40mL), dried (Na₂SO₄), filtered and concentrated to a yellow oil. Thecrude material was treated with excess 3N HCl ethyl acetate andconcentrated, then dissolved in a minimum of CH₂Cl₂ and the solution wassaturated with hexanes and stirred. After stirring 4 hours the productwas collected by filtration (155 mg, 42%). ¹H NMR (free base) (400 MHz,CDCl₃) δ7.15 (m, 2H), 7.09 (d, J=8.0 Hz, 1H), 3.00-2.94 (m, 4H), 2.68,(m, 2H), 2.38 (m, 1H), 1.92 (d, J=10.5 Hz, 1H). ¹H NMR (HCl salt) (400MHz, DMSO-d₆)δ7.30-7.20 (m, 3H), 3.30-3.15 (m, 6H), 2.37 (m, 1H), 1.89(d, J=11.0 Hz, 1H). APCl MS m/e 194.1 [(M+1)^(+].)

EXAMPLE 32 10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIEN-4-YLCYANIDE HYDROCHLORIDE

[0495] A)1-(4-Iodo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

[0496]1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(500 mg, 1.85 mmol) was dissolved in H₂O (5 mL) and concentrated H₂SO4solution (0.5 mL) then cooled to 0° C. and treated with a solution ofsodium nitrite (NaNO₂) (140 mg, 2.04 mmol) in H₂O (2 mL) dropwise.Potassium iodide (460 mg, 2.78 mmol) in 1N H₂SO₄ solution (0.5 mL) wasadded over 10 minutes (reaction becomes dark red). The resultingsolution was warmed to room temperature and stirred 18 hours. Thereaction was quenched with NaHSO₃ and water (pH 2.5) then extracted withethyl acetate (4×30 mL). After drying (Na₂SO₄), the solution wasfiltered and concentrated to a yellow oil which was chromatographed onSilica gel to provide a yellow oil. (260 mg, 37%). (TLC 30% ethylacetate/hexanes R_(f) 0.70). (A 5.4 g scale performed as above yielded 5g, 67%).

[0497] B)4-Iodo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester

[0498]1-(4-Iodo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(5 g, 13.1 mmol) and 37% saturated aqueous NH₄0H solution (50 mL) werestirred in methanol (250 ml) for 2 hours then concentrated andazeotroped with methanol (2×50 mL). The resulting product was stirred in1,4-dioxane (75 mL) and treated with saturated Na₂CO₃ solution (15 mL).To this was added di-t-butyldicarbonate (5.71 g, 26.2 mmol). Afterstirring 18 hours the reaction was treated with H₂O (50 mL) andextracted with CH₂Cl₂ (4×30 mL), dried (Na₂SO₄), filtered, concentratedand chromatographed on Silica gel (TLC 20% ethyl acetate/hexanes) toprovide product as an oil (4.9 g, 98%).

[0499] C)4-Cyano-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (Utilizing the methods described in: House, H. O.;Fischer, W. F. J. Org. Chem. 1969, 3626.)

[0500] CuCN (108 mg, 1.21 mmol) and NaCN (59 mg, 1.21 mmol) werecombined in dry DMF (6 mL) and warmed to 150° C. under N₂. Solutionoccurs in 20 minutes. To this was added4-iodo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (232 mg, 0.6 mmol) in DMF (3.5 mL) and the mixturewas stirred for 18 hours at 150° C. The reaction was cooled and dilutedwith 50% saturated aqueous NaCl solution and extracted with 50% ethylacetate/hexanes (3×30 mL). After drying (Na₂SO₄), filtration andconcentration the product was isolated by chromatography (86 mg, 50%).(TLC 20% ethyl acetate/hexanes R_(f) 0.28).

[0501] D) 10-Azatricyclof6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ylcyanide hydrochloride4-Cyano-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester was treated with 3N HCl ethyl acetate (6 mL) andwarmed to reflux for 2 hours, then concentrated, dissolved in a minimumof methanol which was saturated with Et₂O and stirred 18 hours. Theproduct was collected by filtration (49 mg, 73%). ¹H NMR (400 MHz,DMSO-d₆) δ9.66 (br s, NH), 7.86 (br s, NH), 7.74-7.70 (m, 2H), 7.49 (d,J=7.5 Hz, 1H), 3.33-2.97 (m, 6H), 2.17 (m, 1H), 2.01 (d, J=11.0 Hz, 1H).GCMS m/e 184 (M⁺). M.p. 268-273° C.

EXAMPLE 333-(10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIEN-4-YL)-5-METHYL-1,2,4-OXADIAZOLEHYDROCHLORIDE

[0502]4-Cyano-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (300 mg, 1.1 mmol) was stirred in ethanol (10 mL).To this hydroxyl amine hydrochloride (382 mg, 5.5 mmol) and NaOH (242mg, 6.05 mmol) were added and the mixture was warmed to reflux. After 45minutes, the reaction was cooled, diluted with H₂O and extracted withethyl acetate. The organic layer was dried (Na₂SO₄) and concentrated toafford a yellow solid (110 mg, 0.35 mmol). This solid was dissolved inpyridine (1 mL) and treated with acetyl chloride (0.03 mL, 0.415 mmol)and warmed to 100° C. for 18 hours. The reaction was cooled, treatedwith H₂O and extracted with ethyl acetate. The organic extracts werewashed with water and saturated aqueous NaCl solution, dried (Na₂SO₄)and concentrated. Chromatography on Silica gel afforded product (50 mg,0.15 mmol). (25% ethyl acetate/hexanes R_(f) 0.18). This product wastreated with 2N HCl methanol (10 mL), heated to 70° C. for 1 hour,cooled, concentrated and recrystallized from methanol/Et₂O to provideproduct (15 mg). APCl MS m/e 242.2 [(M+1)^(+].)

EXAMPLE 341-(10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIEN-4-YL)-1-ETHANONEHYDROCHLORIDE

[0503] A)1-(4-Acetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

[0504]1-(10-Aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(253 mg, 1.0 mmol) and AcCl (0.68 mL, 10 mmol) were dissolved in DCE (3mL) and treated with aluminum chloride (AlCl₃) (667 mg, 5.0 mmol). Theresulting yellow mixture was stirred for 30 minutes then poured over iceand saturated aqueous NaHCO₃ solution. After stirring 20 minutes themixture was extracted with CH₂Cl₂ (3×30 mL). The organic layer was driedthrough a cotton plug then concentrated to a orange-yellow oil (255 mg,86%).

[0505] B)4-Acetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester

[0506]1-(4-Acetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(1.3 g, 4.37 mmol) and 37% aqueous NH₄OH solution (10 mL) were stirredin methanol (30 ml) for 3 hours, then concentrated and azeotroped withmethanol (2×50 mL). (This product could be converted to an HCl saltdirectly: see the next example.) The resulting product was stirred in1,4-dioxane (20 mL) and treated with saturated aqueous Na₂CO₃ solution(5 mL). To this was added di-t-butyldicarbonate (1.91 g, 8.74 mmol).After stirring 2 hours, the reaction was treated with H₂O (50 mL),extracted with CH₂Cl₂ (4×30 mL), dried (Na₂SO₄), filtered, concentratedand chromatographed to provide an oil (1.3 g, 100%). (TLC 40% ethylacetate/hexanes R_(f) 0.56).

[0507] C)1-(10-Azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-1-ethanonehydrochloride

[0508]4-Acetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (190 mg, 0.63 mmol) was treated with excess 3N HClethyl acetate and warmed to 70° C. for 1 hour then concentrated anddissolved in a minimum of methanol. The resulting solution was saturatedwith Et₂O and stirred. After 18 hours the white crystalline product wascollected by filtration (81 mg, 54%). ¹H NMR (400 MHz, DMSO-d₆) δ9.75(br s, NH), 7.89 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.74 (br s, NH), 7.44(d, J=8.0 Hz, 1H), 3.33 (br s, 2H), 3.22 (br s, 2H), 3.00 (br m, 2H),2.54 (s, 3H), 2.17 (m, 1H), 2.02 (d, J=11.0 Hz, 1H). GCMS m/e 201 (M⁺).M.p. 198-202° C.

EXAMPLE 35 10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIEN-4-OLHYDROCHLORIDE

[0509] A) Acetic acid10-trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7).3,5-trien-4-ylester

[0510]1-(4-Acetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(2.5 g, 8.41 mmol) and 3-chloroperoxybenzoic acid (m-CPBA) (7.5 g, 42mmol) were stirred in CH₂Cl₂ (20 mL) and warmed to 40° C. for 18 hours.The mixture was cooled to room temperature, then treated withdimethylsulfide (Me₂S) (3 mL, 40.8 mmol) and stirred 24 hours. Theresulting mixture was poured into ice and saturated aqueous Na₂CO₃solution (100 mL) then extracted with Et₂O (4×40 mL). The organic layerwas washed saturated aqueous Na₂CO₃ solution (3×40 mL) then dried(Na₂SO₄), filtered and concentrated to afford an oil (1.83 g, 69%). (TLCethyl acetate R_(f) 0.80).

[0511] B)2,2,2-Trifluoro-1-(4-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone

[0512] Acetic acid10-trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ylester (900 mg, 2.87 mmol) was stirred in methanol (20 mL) and saturatedaqueous NaHCO₃ solution (15 mL) for 48 hours. The mixture wasconcentrated, diluted with H₂O and extracted with CH₂Cl₂ (3×20 mL) thendried through a cotton plug. Chromatography on Silica gel provided pureproduct (420 mg, 54%). (TLC 5% methanol/CH₂Cl₂ R_(f) 0.44). ¹H NMR (400MHz, CDCl₃)δ7.05 (m, 1H), 6.70 (m, 1H), 6.62 (m, 1H), 4.32 (m, 1H), 3.84(m, 1H), 3.48 (m, 1H), 3.21 (br s, 1H), 3.16 (br s, 1H), 3.09 (m, 1H),2.38 (m, 1H), 1.97 (d, J=11.0 Hz, 1H).

[0513] C) 10-Azatricyclo[6.3.1.0^(2,7)]dodeca-2(7)13,5-trien-4-olhydrochloride

[0514]2,2,2-Trifluoro-1-(4-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone(50 mg, 0.184 mmol) was dissolved in methanol/H₂O (3/1, 5 mL), treatedwith Na₂CO₃(s) (40 mg, 0.369 mmol) and warmed to 65° C. for 2 hours. Themixture was concentrated, diluted with H₂O and extracted with CH₂Cl₂(3×20 mL) then dried through a cotton plug. Filtration through a Silicagel plug provided an oil (10% methanol/CH₂Cl₂) which was treated with 3NHCl ethyl acetate (3 mL) then concentrated, dissolved in a minimum ofmethanol which was saturated with Et₂O and stirred. After 18 hours thewhite crystalline product was collected by filtration (10 mg, 26%). ¹HNMR (400 MHz, CDOD₃) δ7.16 (d, J=8.0 Hz, 1H), 6.80 (d, J=2.0 Hz, 1H),6.72 (dd, J=8.0,2.0 Hz, 1H), 3.32-3.28 (4H), 3.09 (dd, J 14.5,12.0 Hz,2H), 2.32 (m, 1H), 2.03 (d, J=11.0 Hz, 1H). APCl MS m/e 176.2 [(M+1)⁺].M.p. 308 (dec.)° C.

EXAMPLE 367-METHYL-5-OXA-6,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]PENTADECA-2,4(8),6,9-TETRAENEHYDROCHLORIDE

[0515] A) 1-(4-Acetyl-5-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

[0516] Acetic acid10-trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ylester (800 mg, 2.55 mmol) was combined with AlCl₃ (1.0 g, 7.65 mmol) andwarmed to 170° C. for 2 hours. The mixture was cooled and treated with1N aqueous HCl solution (20 mL), extracted with ethyl acetate and dried(Na₂SO₄). Chromatography affords an oil (190 mg, 24%). (TLC ethylacetate R_(f) 0.75). ¹H NMR (400 MHz, CDCl₃) δ12.58 (s, 0.5H), 12.52 (s,0.5H), 7.53 (s, 1H), 6.86 (s, 1H), 4.33 (m, 1H), 3.91 (m, 1H), 3.56 (m,1H), 3.28 (br s, 1H), 3.24 (br s, 1H), 3.14 (m, 1H), 2.35 (m, 1H), 1.97(br d, J=11.2 Hz, 1H).

[0517] B)2,2,2-Trifluoro-1-[4-hydroxy-5-(1-hydroxyimino-ethyl)-10-aza-tricyclo[6.3.1.0^(2,7)]-dodeca-2(7),3,5-trien-10-yl]-ethanone

[0518]1-(4-Acetyl-5-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(190 mg, 0.605 mmol), hydroxylamine HCl (99 mg, 1.21 mmol) and sodiumacetate (118 mg, 1.21 mmol) were combined in methanol (4 mL) and H₂O (1mL) and warmed to 65° C. for 18 hours. The mixture was cooled, dilutedwith H₂O and extracted with ethyl acetate which was dried (Na₂SO₄),filtered and concentrated to provide a yellow oil (177 mg, 93%).

[0519] C)2,2,2-Trifluoro-7-Methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),6,9-tetraene-ethanone

[0520] The above oil,2,2,2-trifluoro-1-[4-hydroxy-5-(1-hydroxyimino-ethyl)-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl]-ethanone(177 mg, 0.54 mmol) was stirred in DCE (3 mL), treated withtriethylamine (0.4 mL, 2.8 mmol) and acetic anhydride (Ac₂O) (0.3 mL,2.8 mmol) then stirred 18 hours. The reaction was treated with H₂O andextracted with ethyl acetate. The extracts were dried (Na₂SO₄), filteredand concentrated to a yellow oil which was dissolved in anhydrous DMF (3mL) and treated with 60% NaH in oil (32 mg, 1.08 mmol). After stirring18 hours, additional 60% NaH in oil was introduced (33 mg) and themixture was stirred 2 hours. The reaction was quenched with H₂O (5 mL)and extracted with 80% ethyl acetate/hexanes (3×30 mL). The organiclayer was washed with H₂O (3×20 mL), dried (Na₂SO₄), filtered andconcentrated and chromatographed to provide an oil (40% ethylacetate/hexanes R_(f) 0.56).

[0521] D)7-Methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0^(2,10.)0^(4,8)]pentadeca-2,4(8),6,9-tetraenehydrochloride

[0522] Utilizing the methods described in Example 9C,2,2,2-Trifluoro-7-Methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),6,9-tetraene-ethanonewas converted to the title compound. This was treated with 3N HCl ethylacetate (3 mL), concentrated and dissolved in a minimum of CH₂Cl₂ whichwas saturated with hexanes and stirred. After 18 hours the whitecrystalline product was collected by filtration (18 mg, 13% overall). ¹HNMR (400 MHz, DMSO-d₆) δ7.72 (s,1H), 7.63 (s, 1H), 3.42-2.98 (m, 6H),2.50 (s, 3H), 2.23 (m, 1H), 2.08 (d, J=10.5 Hz, 1H). APCl MS m/e 215.2[(M+1)⁺].

EXAMPLE 374-(2-METHYL-2H-PYRAZOL-3-YL)-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE and4-(1-METHYL-1H-PYRAZOL-3-YL)-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

[0523]1-(4-Acetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(1.0 g, 3.3 mmol) and dimethylformamide dimethylacetal (DMF-DMA) (4.0 g,33.6 mmol) were warmed to 140° C. for 18 hours. After cooling, acrystalline precipitate was filtered and rinsed with ethyl acetate (690mg, 58%).

[0524] The above solid,3-dimethylamino-1-(10-trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]-dodeca-2(7),3,5-trien-4-yl)-propenone,(200 mg, 0.56 mmol) was dissolved in ethanol (2 mL) and treated with 5NHCl ethanol (0.1 mL) followed by methyl hydrazine (0.6 mmol). Theresulting mixture was warmed to 70° C. for 4 hours. The mixture wascooled, diluted with water and extracted with ethyl acetate, dried(Na₂SO₄) and concentrated. Chromatography on Silica gel provided a 3/1mixture of regioisomeric products (130 mg, 68%). (TLC 50% ethylacetate/hexanes R_(f) 0.40).

[0525] The above oil (130 mg, 0.388 mmol) and Na₂CO₃(s) (82 mg, 0.775mmol) were stirred in methanol (10 mL) and H₂O (5 mL) for 18 hours.After cooling the reaction was diluted with water, extracted with CH₂Cl₂dried through a cotton plug and concentrated. The product was purifiedby chromatography on Silica gel and concentrated to an oil. The salt wasgenerated with 2N HCl methanol, concentrated and recrystallized frommethanol/ethyl acetate to provide a 3/1 mixture of regioisomericpyrrazoles (85 mg, 58%). (5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.25).TFA-precursor APCl MS m/e 336.2 [(M +1)⁺].

EXAMPLE 384,5-DICHLORO-10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

[0526] A)1-(4,5-Dichloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(Based on Campaigne, E.; Thompson, W. J. Org. Chem. 1950, 72, 629.)

[0527]1-(10-Aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(539 mg, 2.1 mmol) was stirred in CH₂Cl₂ (5 mL) and treated with lCl₃(s) (982 mg, 4.21 mmol). The resulting orange solution was stirred 0.5hours, poured into saturated aqueous NaHSO₃ solution (25 mL), extractedwith CH₂Cl₂ (3×25 mL), dried through a cotton plug and concentrated toan oil (570 mg, 84%) (TLC 50% ethyl acetate/hexanes R_(f) 0.62).

[0528] B)4,5-dichloro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride

[0529]1-(4,5-Dichloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(570 mg, 1.75 mmol) was stirred in methanol (25mL) and treated withNa₂CO₃(s) (5 g, 47 mmol) in H₂O (5 mL). The stirred mixture was warmedto 70° C. for 4 hours, concentrated to solids, diluted with H₂O andextracted with ethyl acetate (3×40 mL). The product was extracted into1N aqueous HCl solution (2×40 mL) which was washed with ethyl acetatethen neutralized with saturated aqueous Na₂CO₃ solution to pH-10.Product was extracted with CH₂Cl₂ (3×40 mL), filtered through a cottonplug and concentrated to an oil (400 mg, 100%).

[0530] The oil was dissolved in methanol and treated with 3N HCl ethylacetate (4 mL) and concentrated, then dissolved in a minimum of methanoland which was saturated with Et₂O and stirred 18 hours. The product wascollected by filtration (210 mg, 45%). (TLC 50% ethyl acetate/hexanes(NH₃) R_(f) 0.08). ¹H NMR (400 MHz, DMSO-d₆) δ7.58 (s, 2H), 3.33-2.97(m, 6H), 2.18 (m, 1H), 1.99 (d, J=10.5 Hz, 1H). ¹³C NMR (100MHz,DMSO-d₆)δ141.02, 130.60, 126.58, 45.54, 40.55, 38.30. GCMS m/e 227,229 (M⁺). M.p. 283-291° C.

EXAMPLE 39N⁴,N⁴-DIMETHYL-10-AZATRICYCLO[6.3.1.0^(2,7)]-DODECA-2(7),3,5-TRIENE-4-SULFONAMIDEHYDROCHLORIDE

[0531] A)10-Trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonylchloride

[0532]1-(10-Aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(530 mg, 2.1 mmol) was added to chlorosulfonic acid (2 mL, 30 mmol) andstirred for 5 minutes. The mixture was quenched with ice, extracted withethyl acetate, dried (Na₂SO₄), filtered and concentrated to provide anoil (640 mg, 87%). (TLC 30% ethyl acetate/hexanes R_(f) 0.15).

[0533] B) N⁴N⁴-Dimethyl-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonamidehydrochloride

[0534]10-Trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonylchloride (320 mg, 0.9 mmol) was stirred in THF (10 mL) and treated with40% Me₂NH/H₂O (1.5 mL). After 10 minutes the mixture was concentratedand chromatographed on Silica gel (TLC 30% ethyl acetate/hexanes R_(f)0.31) to provide an oil (256 mg, 78%). This material was dissolved inmethanol (6 mL) and NH₄OH (2 mL) and stirred 18 hours. The mixture wasconcentrated and azeotroped from methanol (3 times) The resulting oilwas dissolved in methanol and treated with 3N HCl ethyl acetate (4 mL),concentrated, dissolved in a minimum of methanol and which was saturatedwith Et₂O and stirred 18 hours. The product was collected by filtrationas a white powder (163 mg, 59%). (TLC 10% methanol/CH₂Cl₂ (NH₃) R_(f)0.54). ¹H NMR (data, free base) (400 MHz, CDCl₃) δ7.64 (m, 2H), 7.41 (d,J=8.0 Hz, 1H), 3.30 (m, 2H), 3.20 (d, J=12.5 Hz, 2H), 3.07 (dd,J=12.5,2.2 Hz, 2H), 2.69 (s, 6H), 2.45, (m, 1H), 2.00 (d, J=11.0 Hz,1H). ¹³C NMR (100 MHz, CDCl₃)δ128,43, 124.16, 122,75, 46.67, 46.55,42.11, 39,44, 37,81. GCMS m/e 266 (M⁺). (data HCl salt) ¹H NMR (400 MHz,DMSO-d₆) δ7.68-7.52 (3H), 3.38 (m, 2H), 3.24 (m, 2H), 3.04 (m, 2H), 2.58(s, 6H), 2.22 (m, 1H), 2.04 (d, J=11.0 Hz, 1H). GCMS m/e 266 (M⁺). Anal.Calcd. for C₁₃H,₈N₂O₂HCl: C, 51.56; H, 6.32; N, 9.25. Found C, 51.36;H,6.09; N,9.09.

EXAMPLE 404-(1-PYRROLIDINYLSULFONYL)-10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

[0535] The pyrrolidine analogue was prepared from10-trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonylchloride (320 mg, 0.9 mmol) as by substituting pyrroline in the couplingstep described in Example 39B. The TFA product was isolated as an oil(314 mg, 89%). Deprotection and conversion to the salt as in Example 39Baffords a white powder (189 mg, 63%). (TLC 10% methanol/CH₂Cl₂ (NH₃)R_(f) 0.60). (TLC 50% ethyl acetate/hexanes R_(f) 0.65). ¹H NMR (400MHz, CDCl₃) δ7.66 (d, J=8.0 Hz, 1H), 7.64 (s, 1H), 7.37 (d, J=8.0 Hz,1H), 3.30-3.15 (m, 8H), 3.00 (m 2H), 2.39 (m, 1H), 1.98 (d, J=11.5 Hz,1H), 1.72 (m, 4H). ¹³C NMR (100 MHz, CDCl₃) δ146.91, 144.08, 136.65,127. 90, 124.18, 122.36, 50.43, 47.87, 46.80, 46.63, 42.11, 39.63,25.10. APCl MS m/e 293 [(M+1)⁺]. (data HCl salt) ¹H NMR (400 MHz,DMSO-d₆) δ9.78 (br s, NH), 8.1 (br s, NH), 7.73 (d, J=1.5 Hz,1H), 7.66(dd, J=8.0,1.5 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 3.39-3.01 (1OH), 2.21(m, 1H), 2.04 (d, J=11.0 Hz, 1H), 1.66 (m, 4H). GCMS m/e 292 (M⁺). Anal.Calcd. For C₁₃H₁₈N₂O₂HCl.½methanol: C, 54.07; H, 6.47; N, 8.51. Found C,53.98; H,6.72; N, 8.12

EXAMPLE 415,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]PENTADECA-2,4(8),9-TRIEN-6-ONEHYDROCHLORIDE

[0536] (The title compound was prepared following the proceduresdescribed in Quallich, G. J.; Morrissey, P. M. Synthesis 1993, 51-53,treating4,5-dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester as an equivalent to an ortho fluoro phenylmoiety.) ¹H NMR (400 MHz, DMSO-d₆) δ10.42 (s, NH), 9.88 (br s, NH), 7.52(br s, 1H), 7.15 (s, 1H), 6.79 (s, 1H), 3.41 (d, J=5.0 Hz, 2H),3.35-3.13 (m, 4H), 2.93 (m, 2H), 2.12 (m, 1H), 1.95 (d, J=11.5 Hz, 1H).APCl MS m/e 215.2 [(M+1)⁺].

EXAMPLE 426-OXO-5-OXA-7,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,6,8-TETRAENEHYDROCHLORIDE

[0537] (For references, see: Nachman, R. J. J. Het. Chem. 1982, 1545.)2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone(317 mg, 1.11 mmol) was stirred in THF (10 mL), treated withcarbonyidiimidazole (269 mg, 1.66 mmol) and warmed to 60° C. for 18hours. The mixture was concentrated, diluted with CH₂Cl₂ (50 mL) andwashed with 1N aqueous HCl solution (3×10 mL). The organic layer wasdried through a cotton plug, concentrated and chromatographed on Silicagel (50% ethyl acetate/Hexanes) to provide an oil (130 mg). Thismaterial converted to the title compound by the methods described inExample 9C. ¹H NMR (400 MHz, DMSO-d₆) δ11.78 (s, NH), 9.56 (br s, NH),7.63 (br s, NH), 7.24 (s, 1H), 7.07 (s,1H), 3.26 (br s, 2H), 3.16 (br t,J=9.5 Hz, 1H), 2.93 (br s, 1H), 2.18 (m, 1H), 1.97 (d, J=11.0 Hz, 1H).APCl MS m/e 217.2 [(M+1)⁺].

EXAMPLE 436-BENZYL-5-OXA-7,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,6,8-TETRAENEHYDROCHLORIDE

[0538]2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanoneand phenyl-acetyl chloride were converted to the title compoundfollowing the procedures described in Example 47. ¹H NMR (400 MHz,CD₃OD) δ7.63 (s, 1H), 7.58 (s, 1H), 7.36-7.24 (5H), 4.29 (s, 2H), 3.46(d, J=2.5 Hz, 2H), 3.39 (d, J=12.0 Hz, 2H), 3.18 (2H), 2.42 (m, 1H),2.15 (d, J=11.5 Hz, 1H). APCl MS m/e 291.2 [(M+1)⁺].

EXAMPLE 44 3-PHENYL-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

[0539] A) 5-Fluoro-1,4-dihydro-1,4-methano-naphthalene and5-iodo-1,4-dihydro-1,4-methano-naphthalene

[0540] (Eisch, J. J.; Burlinson, N. E. J. Amer. Chem. Soc. 1976, 98,753-761. Paquette, L. A.; Cottrell, D. M.; Snow, R. A. J. Amer. Chem.Soc. 1977, 99, 3723-3733.)

[0541] Magnesium turnings (9.37 g, 385 mmol) were stirred in anhydrousTHF (1000 mL) in a flame dried 2L 3 neck round bottom flask equippedwith a non-equalizing addition funnel with a N₂ flow adapter, magneticstirrer and efficient condenser equipped with a N₂ flow adapter. Theflask was stirred and warmed to reflux by a removable heating mantle.2,6-Difluoro-iodobenzene (0.3 g) was added followed by of 3N EtMgBr inTHF (0.3 mL). The addition funnel was charged with an intimate mixtureof cyclopentadiene (24.24 g, 367 mmol) and 2,6-difluoro-iodobenzene(88.0 g, 367 mmol). Small portions (˜1 mL) of the intimate mixture wereintroduced to assist initiation (˜4 times). After ˜15 minutes, thereaction initiated (exotherm, and vapor condensation) and heating wasmaintained as necessary during the addition of the contents of theaddition funnel. The reaction was then maintained at reflux for ˜1 hour(no SM by GCMS).

[0542] The reaction was cooled to room temperature and quenched with H₂O(200 mL) followed by aqueous 1 N HCl solution (200 mL) to dissolve thesolids. Product was extracted with hexanes (4×150 mL). The combinedorganic layer was washed with saturated aqueous NaHCO₃ solution (150mL), dried (Na₂SO₄), filtered through a Silica plug with hexanes rinseand concentrated to an oil (70 g). Chromatography on Silica gel elutingwith hexanes provided two lots (9.0 and 21.0 g), which containedprimarily 5-iodo-1,4-dihydro-1,4-methano-naphthalene. (TLC hexanes R_(f)0.63).

[0543] B) 5-Iodo-1,2,3,4-tetrahydro-1,4-methano-naphthalene-2,3-diol

[0544] 5-Iodo-1,4-dihydro-1,4-methano-naphthalene (20 g) and N-methylmorpholine N-oxide (17.61 g, 130 mmol) were stirred in acetone (90 mL)and H₂O (13 mL). To this was added a solution of OsO₄ (0.2 mL, 2.5%wt.solution in t-butanol, 0.02 mmol). After 144 hours, Florisil (5 g) andsaturated aqueous NaHSO₃ solution (3 mL) were added and stirred for 1/2hour. The mixture was filtered through a Celite pad and the filtrateconcentrated to produce an oil which was purified by chromatography onSilica gel eluting with a gradient of hexanes to 100% ethyl acetate toprovide a yellow solid (13.73 g). APCl MS m/e 301.1 [(M−1)⁺].

[0545] C)10-Benzyl-3-iodo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

[0546] 5-lodo-1,2,3,4-tetrahydro-1,4-methano-naphthalene-2,3-diol (8.33g, 27.6 mmol) and Et₃NBnCl (10 mg) were vigorously stirred indichloroethane (25 mL) and H₂O (75 mL) then treated with sodiumperiodate (6.17 g, 29.0 mmol). After 1.5 hours, the layers wereseparated and the aqueous layer extracted with DCE (2×40 mL). Thecombined organic layer was washed with H₂O (4×30 mL) until no reactionto starch iodide paper was observed, then with saturated aqueous NaClsolution (30 mL). The organic layer was dried through a cotton plug andtreated with benzyl amine (3.16 mL, 29.0 mmol) and stirred for 2 minutesthen transferred to an addition funnel. This solution was added over 10minutes to a vigorously stirred cooled (0° C.) mixture of NaHB(OAc)₃(18.72 g, 88.0 mmol) in DCE (150 mL). After addition was complete, themixture was stirred without cooling for 2 hours. The mixture wasquenched with saturated aqueous Na₂CO₃ solution (100 mL) and stirred for1 hour, then the layers were separated and the aqueous layer wasextracted with CH₂Cl₂ (3×50 mL). The combined organic layer was washedwith saturated aqueous NaCl solution (50 mL), dried through a cottonplug and concentrated. Chromatography on Silica gel provided an oil (6.3g, 61%). (TLC 5% ethyl acetate/hexanes R_(f) 0.10). ¹H NMR (400 MHz,CDCl₃) δ7.61 (d, J=8.0 Hz, 1H), 7.28-7.22 (m, 3H), 7.13 (d, J=8.0Hz,1H), 6.98-6.94 (m, 3H), 3.58 (AB dd, J=14.2 Hz, 2H), 3.26 (br s, 1H),3.21 (br s, 1H), 3.04 (br d, J=10.2 Hz, 1H), 2.83 (br d, J=10.2 Hz, 1H),2.47 (d, J=10.0 Hz, 1H), 2.39 (d, J=10.0 Hz, 1H), 2.34 (m, 1H), 1.72 (d,J=10.5 Hz, 1H). APCl MS m/e 376.0 [(M+1)⁺].

[0547] D)10-Benzyl-3-phenyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

[0548] (For a discussion, see: Miyaura, N.; Suzuki, A. Chem. Rev. 1995,95, 2457-2483.)10-Benzyl-3-iodo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene(375.3 mg, 1.0 mmol), potassium acetate (785 mg, 8.0 mmol) and phenylboronic acid (183 mg, 1.5 mmol) were combined in 10/1 ethanol/H₂O (5mL). The mixture was degassed (3 vacuum/N₂ cycles), treated withtetrakis(triphenylphosphine)palladium(0) (57.5 mg, 0.05 mmol) and warmedto 90° C. for 18 h. The reaction was cooled, diluted with H₂O andextracted with Et₂O (3×50 mL). The organic layer was washed with brine(50 mL), dried (MgSO₄), filtered and concentrated to provide an oil (180mg, 55%). (TLC 4% ethyl acetate/hexanes R_(f) 0.18). GCMS m/e 325 (M)⁺.

[0549] E) 3-Phenyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride

[0550]10-Benzyl-3-phenyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienewas converted into the title compound utilizing the conditions describedin Example 2D. (TLC 10% methanol/CH₂Cl₂ (NH₃) R_(f) 0.30). (data forfree base) ¹H NMR (400 MHz, CDCl₃) δ7.46-7.15 (8H), 3.17 (br s, 1H),3.01 (m, 2H), 2.93 (d, J=13.0 Hz, 1H), 2.72 (dd, J=10.5,2.5 Hz, 1H),2.63 (dd, J=10.5,2.5 Hz, 1H), 2.41 (m, 1H), 1.91 (d, J=10.5 Hz, 1H).APCl MS m/e 236.2 [(M+1)⁺]. (HCl salt) M.p. 262-265° C. Anal. Calcd. forC₁₇H₁₇N.HCl.⅓H₂O C, 73.26; H, 6.86; N, 5.19. Found C, 73.50; H, 6.77; N,5.04.

EXAMPLE 453-HYDROXY-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

[0551] A) 10-Benzyl-3-boronicacid-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene10-Benzyl-3-iodo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene(3.0 g, 7.99 mmol) was stirred in anhydrous THF (40 mL) at −78° C. undernitrogen and treated dropwise with n-BuLi (3.84 mL of 2.5M solution inhexanes, 9.59 mmol). After 10 minutes, tri-isopropylborate (4.61 mL,20.0 mmol) was added dropwise. After ˜½ hour, the reaction was pouredinto saturated aqueous NaHCO₃ solution, stirred 5 minutes and extractedwith ethyl acetate (3×50 mL) and concentrated. The residue was dissolvedin 30% Et₂O/hexanes and extracted with 1 N NaOH aqueous solution (4×50mL). The combined aqueous basic layer was treated with concentrated HClto achieve pH 8 and extracted with ethyl acetate (4×25 mL), dried(Na₂SO₄) and stripped. Chromatography on Silica gel eluting first with3% ethyl acetate/hexanes to remove non-polar components, then with 5%methanol/CH₂Cl₂ provides the title compound. (TLC 25% ethylacetate/hexanes R_(f) 0.60).

[0552] B)10-Benzyl-3-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

[0553] 10-Benzyl-3-boronicacid-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene (140 mg, 0.48mmol) dissolved in THF (5 mL) was treated withN-methylmorpholine-N-oxide (64.5 mg, 0.48 mmol) and brought to refluxfor 1 hour. The reaction was concentrated and chromatographed on Silicagel to provide product. (TLC 25% ethyl acetate/hexanes R_(f) 0.18). ¹HNMR (400 MHz, CDCl₃) δ7.18-7.15 (3H), 7.04 (dd, J=8.0,7.0 Hz, 1H), 6.95(m, 2H), 6.75 (d, J=7.0 Hz, 1H), 6.59 (dd, J=8.0,1.0 Hz, 1H), 3.53 (br5, OH), 3.51 (AB d, J=14.0 Hz, 2H), 3.28 (br s, 1H), 3.06 (br s, 1H),2.91 (dd, J=8.5,1.5 Hz, 1H), 2.79 (ddd, J=8.5,1.5,1.5 Hz, 1H), 2.42 (d,J=11.0 Hz, 1H), 2.39 (d, J=11.0 Hz, 1H), 2.23 (m, 1H), 1.65 (d, J=10.5Hz, 1H). APCl MS m/e 266.5 [(M+1)^(]).

[0554] C) 3-Hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride

[0555]10-Benzyl-3-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene(160 mg, 0.60 mmol) was converted into the title compound by the methodsdescribed in Example 1D. ¹H NMR (400 MHz, CDCl₃) δ7.15 (dd, J=8.0,7.5Hz, 1H), 6.84 (d, J=7.5 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 3.51 (br s,1H), 3.33-3.25 (3H), 3.16 (d, J=12.0 Hz, 1H), 3.09 (d, J=12.0 Hz, 1H),2.29 (m, 1H), 2.02 (d, J=11.0 Hz, 1H). APCl MS m/e 175.8 [(M+1)⁺]. (HClsalt) M.p. 253-255° C.

EXAMPLE 464,5-DIFLUORO-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

[0556] The title compound was prepared by the methods described inExamples 1 and 2 starting with 2,4,5-trifluorobromobenzene. ¹H NMR (400MHz, CDCl₃) δ7.31 (t, J=8.5 Hz, 2H), 3.48-3.13 (6H), 2.38 (m, 1H), 2.11(d, J=11.5 Hz, 1H). APCl MS m/e 196.2 [(M+1)⁺]. (HCl salt) M.p. 301-303OC. Anal. Calcd. for C₁₁H₁₁F₂N.HCl.⅙H₂O C, 56.30; H, 5.30; N, 5.97.Found C, 56.66; H, 5.41; N, 5.96.

EXAMPLE 47 6-ETHYL-5-OXA-7,13-DIAZATETRACYCLO[9.3.1.0^(2,10) .O^(4,8)]-PENTADECA-2(10),3,6,8-TETRAENE HYDROCHLORIDE

[0557]2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanoneand propionyl chloride were converted to the title compound followingthe procedures described in Example 30 and Goldstein, S. W.; Dambek, P.J. J. Het. Chem. 1990, 27, 335. ¹H NMR (400 MHz, CD₃OD) δ7.64 (s, 1H),7.62 (s, 1H), 3.48 (d, J=2.5 Hz, 2H), 3.41 (d, J=12.0 Hz, 2H), 3.20(2H), 3.01 (q, J=7.5 Hz, 2H), 2.45 (m, 1H), 2.17 (d, J=11.5 Hz, 1H),1.42 (t, J=7.5 Hz, 3H). APCl MS m/e 229.2 [(M+1)⁺].

EXAMPLE 486-ISOPROPYL-5-OXA-7,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,6,8-TETRAENEHYDROCHLORIDE

[0558]2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanoneand isobutyryl chloride were converted to the title compound followingthe procedures described in Example 47. (TLC 25% ethyl acetate/hexanesR_(f) 0.14). ¹H NMR (400 MHz, CD₃OD) δ7.65 (2H), 3.49 (br s, 2H), 3.41(d, J=12.0 Hz, 2H), 3.33-3.19 (3H), 2.45 (m, 1H), 2.18 (d, J=11.5 Hz,1H), 1.45 (d, J=7.0 Hz, 6H). APCl MS m/e 243.2 [(M+1 )⁺]. (HCl salt)M.p. 249-251° C.

EXAMPLE 495,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE

[0559] A)1-(5,14-Diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone(Based on the method of Campbell, K. N.; Schaffner, I. J. J. Am. Chem.Soc. 1945, 67, 86.)

[0560]1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(607 mg, 1.98 mmol) was dissolved in 95% ethanol/H₂O (5 mL) and treatedwith FeCl₃.6H₂O (800 mg, 2.97 mmol), ZnCl₂ (27 mg, 0.20 mmol) in ethanol(2 mL). The mixture was warmed to 65° C. for 15 min., treated withacrolein (0.2 mL, 2.97 mmol) and warmed to reflux for 2.5 hours. Themixture was judged complete by TLC, cooled and quenched into saturatedaqueous NaHCO₃ solution (40 mL). The mixture (pH 8.5) was extracted withCH₂Cl₂ (8×30 mL). The organic layer was washed with H₂O and saturatedaqueous NaCl solution then dried through a cotton plug. Concentrationafforded a dark oil which was chromatographed on Silica gel to provide ayellow oil (105 mg, 17%). (TLC 50% ethyl acetate/hexanes R_(f) 0.08).

[0561] B)5,14-Diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11)3,5,7,9-Pentaenehydrochloride

[0562]1-(5,14-Diazatetracyclo[10.3.10^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone(94.7 mg, 0.31 mmol) was converted to the title compound using methodsdescribed in Example 7 to provide a crystalline solid (36.9 mg). ¹H NMR(400 MHz, CD₃OD) δ9.19 (m, 2H), 8.33 (s, 1H), 8.27 (s, 1H), 8.10 (dd,J=8.3, 5.6 Hz, 1H), 3.78 (br s, 1H), 3.74 (br s, 1H), 3.58 (br d, J=11.4Hz, 2H), 3.40 (M, 2H), 2.50 (m, 1H), 2.34 (d, J=11.6 Hz, 1H). APCl MSm/e 210.9 [(M+1)⁺]; M.p. 260° C. (dec.); Anal. Calcd. for C₁₄H₁₄N₂.2HCl:C, 59.38; H, 5.69; N, 9.89. Found C, 59.69; H, 5.82; N, 9.79.

EXAMPLE 506-METHYL-5,14-DIAZATETRACYCLO[0.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE

[0563] A)1-((6-Methyl-5,14-diazatetracyclo[0.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone

[0564] Following the method described in Example 49A,1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(686. mg, 2.00 mmol) was reacted with (E)-2-butenal (0.2 mL, 2.97 mmol)to provide a yellow oil. (335.6 mg, 52%). (TLC 75% ethyl acetate/hexanesR_(f) 0.25).

[0565] B)6-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-Pentaenehydrochloride

[0566]1-(6-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone(308 mg, 0.96 mmol) was converted to the title compound using methodsdescribed in Example 7 to provide a crystalline solid (186 mg). ¹H NMR(400 MHz, CD₃OD) δ9.00 (d, J=8.5 Hz, 1H), 8.25 (s, 1H), 8.17 (s, 1H),7.94 (d, J=8.5 Hz, 1H), 3.76 (br s, 1H), 3.71 (br s, 1H), 3.57 (br d,J=11.8 Hz, 2H), 3.38 (M, 2H), 3.01 (s, 3H), 2.49 (m, 1H), 2.32 (d,J=11.6 Hz, 1H). APCl MS m/e 225.2 [(M+1)⁺]; M.p.>300° C. (dec.); Anal.Calcd. for C₁₅H₁₆N₂.2HCl.½H₂O C, 58.83; H, 6.25; N, 9.15. Found C,58.49; H, 6.22; N, 9.02.

EXAMPLE 517-METHYL-5,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE

[0567] A)1-(7-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-Pentaen-10-yl)-2,2,2-trifluoro-ethanone

[0568] Following the method described in Example 49A,1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(686 mg, 2.00 mmol) was reacted with 2-methylpropenal (0.25 mL, 3.00mmol) to provide a yellow oil (94 mg, 15%). (TLC 10% methanol/CH₂Cl₂R_(f) 0.16).

[0569] B)7-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9])hexadeca-2(11),3,5,7,9-pentaenehydrochloride

[0570]1-(7-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone(86 mg, 0.27 mmol) was converted to the title compound using methodsdescribed in Example 7 to provide a crystalline solid (12.6 mg). ¹H NMR(400 MHz, CD₃OD) δ9.10 (s, 1H), 9.00 (s, 1H), 8.22 (s, 1H), 8.20 (s,1H), 3.76 (br s, 1H), 3.72 (br s, 1H), 3.57 (br d, J=11.5 Hz, 2H), 3.39(M, 2H), 2.71 (s, 3H), 2.48 (m, 1H), 2.32 (d, J=11.6 Hz, 1H). APCl MSm/e 225.0 [(M+1)⁺].

EXAMPLE 527-ETHYL-5,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE

[0571] A)1-(7-Ethyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone

[0572] Following the method described in Example 49A,1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(686 mg, 2.00 mmol) was reacted with 2-ethylpropenal (0.35 mL, 3.60mmol) to provide a yellow oil (110 mg, 16%). (TLC 75% ethylacetate/hexanes R_(f) 0.32).

[0573] B)7-Ethyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaenehydrochloride

[0574]1-(7-Ethyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone(94 mg, 0.28 mmol) was converted to the title compound using methodsdescribed in Example 7 to provide a crystalline solid (33 mg). ¹H NMR(400 MHz, CD₃OD) δ9.12 (s, 1H), 9.00 (s, 1H), 8.23 (s, 1H), 8.18 (s,1H), 3.76 (br s, 1H), 3.72 (br s, 1H), 3.56 (br d, J=11.5 Hz, 2H), 3.37(M, 2H), 3.05 (q, J=7.5 Hz, 2H), 2.48 (m, 1H), 2.32 (d, J=11.6 Hz, 1H),1.44 (t, J=7.5 Hz, 3H). APCl MS m/e 239.1 [(M+1)⁺]; M.p. 288-291° C.(dec.); Anal. Calcd. for C₁₆H₁₈N₂.2HCl.H₂O: C, 58.36; H, 6.73; N, 8.51.Found C, 57.98; H, 5.99; N, 8.41.

EXAMPLE 538-METHYL-5,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE

[0575] A)1-(8-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone

[0576] Following the method described in Example 49A,1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(775 mg, 2.52 mmol) was reacted with 1-buten-3-one (0.32 mL, 3.79 mmol)to provide a yellow oil. (424 mg, 52%). (TLC 50% ethyl acetate/hexanesR_(f) 0.08).

[0577] B)8-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaenehydrochloride

[0578]1-(8-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone(403 mg, 1.26 mmol) was converted to the title compound using methodsdescribed in Example 7 to provide a crystalline solid (266 mg). ¹H NMR(400 MHz, CD₃OD) δ9.01 (d, J=5.6 Hz, 1H), 8.49 (s, 1H), 8.22 (s, 1H),7.97 (d, J=5.6 Hz, 1H), 3.76 (br m, 2H), 3.58 (br d, J=11.5 Hz, 2H),3.40 (m, 2H), 3.06 (s, 3H), 2.48 (m, 1H), 2.33 (d, J=11.6 Hz, 1H). Anal.Calcd. for C₁₅H₁₆N₂.2HCl.H₂O: C, 57.15; H, 6.39; N, 8.89. Found C,57.43; H, 6.44; N, 8.82.

EXAMPLE 545,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,7,9-TETRAEN-6-ONEHYDROCHLORIDE

[0579] A) 3.3-Dimethoxypropanoic acid lithium salt

[0580] (Related to methods described in Alabaster, C. T. et. aL., J.Med. Chem. 1988, 31, 2048-2056.) 3,3-Dimethoxypropanoic acid methylester (14.25 g, 96.2 mmol) in THF (100 mL) was treated with LiOH.H₂O(2.5 g, 106 mmol) and H₂O (2 mL). The mixture was brought to reflux for4 hours, cooled to room temperature and azeotropically dried from THF (4times) to provide white solids (13.3 g).

[0581] B)1-(4-(N-3′,3′-Dimethoxy-propionamide)-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

[0582] 3,3-Dimethoxypropanoic acid lithium salt (840 mg, 6.0 mmol) inTHF (15 mL) was treated with trifluoroacetic anhydride (0.85 mL, 6.0mmol) dropwise and stirred for 15 minutes. The resulting yellow solutionwas added dropwise to a vigorously stirred mixture of1-(4-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(540 mg, 2 mmol) in THF (5 mL) and saturated aqueous NaHCO₃ solution (2mL). After 3 hours the reaction mixture was diluted with H₂O andextracted with ethyl acetate (3 times). The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated to an oil whichwas purified by chromatography on Silica gel to provide a white solid(477 mg, 62%). (TLC 50% ethyl acetate/hexanes R_(f) 0.37).

[0583] C)1-(5,14-Diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one-10-yl)-2,2,2-trifluoro-ethanone

[0584]1-(4-(N-3′,3′-Dimethoxy-propionamide)-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(460 mg, 1.19 mmol) was treated with trifluoroacetic acid (4mL) andstirred 18 hours, concentrated, diluted with CH₂Cl₂ and H₂O. The aqueouslayer was extracted with CH₂Cl₂ (4 times) and the organic layer waswashed with saturated aqueous NaHCO₃ solution (40 mL) and saturatedaqueous NaCl solution then dried through a cotton plug. Concentrationafforded a yellow solid (320 mg, 83%).

[0585] D)5,14-Diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-onehydrochloride

[0586]1-(5,14-Diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one-10-yl)-2,2,2-trifluoro-ethanone(540 mg, 2 mmol) was converted to the title compound using methodsdescribed in Example 7 to provide the title compound a pink crystallinesolid (72 mg, 71%). ¹H NMR (400 MHz, CD₃OD) δ8.42 (d, J=8.8 Hz, 1H),7.90 (s, 1H), 7.66 (s, 1H), 6.98 (d, J=8.8 Hz, 1H), 3.59 (br s, 1H),3.56 (br s, 1H), 3.49 (dd, J=12.4, 5.8 Hz, 2H), 3.29 (m, 2H), 2.42 (m,1H), 2.23 (d, J=11.6 Hz, 1H). APCl MS m/e 227 [(M+1)⁺]; M.p. 300° C.(dec.); Anal. Calcd. for C₁₄H₁₄N₂O.2HCl: C, 56.20; H, 5.39; N, 9.36.Found C, 56.40; H, 5.63; N, 9.25.

EXAMPLE 55 6-CHLORO-5,14-DIAZATETRACYCLO10.3.1.0^(2,11).0^(4,9)1HEXADECA-2(11),3,5,7,9-PENTAENE HYDROCHLORIDE

[0587] A)1-(6-Chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone

[0588]1-(5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one-10-yl)-2,2,2-trifluoro-ethanone(156 mg, 0.49 mmol) was treated with POCl₃ (5 mL) and warmed to 100° C.with stirring for 3 hours. After concentration in vacuo, the residue wasdiluted with CH₂Cl₂ (15 mL) and carefully treated with saturated NaHCO₃solution (10 mL) with stirring. Once CO₂ evolution slowed the mixturewas separated and the aqueous layer extracted CH₂Cl₂ (3 times). Theorganic layer was washed with H₂O and saturated NaCl solution, filteredthrough cotton and concentrated to a brown oil (217 mg, 93%). (TLC ethylacetate, R_(f) 0.3) ¹H NMR (400 MHz, ²HCCl₃) δ8.03 (d, J=8.5 Hz, 1H),7.83 (s, 1H), 7.62 (s, 1H), 7.35 (d, J=8.5 Hz, 1H), 4.43 (m, 1H), 4.01(m, 1H), 3.62 (m, 1H), 3.29 (m, 2H), 3.23 (m, 1H), 2.45 (m, 1H), 2.10(d, J=11.6 Hz, 1H). APCl MS m/e 341.1 [(M+1)⁺].

[0589] B)6-Chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-Pentaenehydrochloride

[0590]1-(6-Chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone(26 mg, 0.076 mmol) was converted to the title compound using methodsdescribed in Example 7 to provide the title compound a solid (5.8 mg,24%). ¹H NMR (free base, 400 MHz, ²HCCl₃) δ8.01 (d, J=8.5 Hz, 1H), 7.77(s, 1H), 7.57 (s, 1H), 7.30 (d, J=8.5 Hz, 1H), 3.28 (br s, 1H), 3.24 (brs, 1H), 3.12 (br d, J=12.5 Hz, 2H), 2.96 (brd, J=12.5 Hz, 2H), 2.41 (m,1H), 2.02 (d, J=11.6 Hz, 1H). APCl MS m/e 245.1 [(M+1)⁺].

EXAMPLE 566-METHOXY-5,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE

[0591] A)6-Chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-carboxylicacid tert-butyl ester

[0592]6-Chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene(2.82 g, 11.53 mmol) was converted into the title compound as describedin Example 12 A to provide a brown oil (3.55 g, 89%). (TLC: 5%methanol/CH₂Cl₂, R_(f) 0.37).

[0593] B)6-Methoxy-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-carboxylicacid tert-butyl ester

[0594] Sodium metal (˜12 mg) was dissolved in methanol (1 mL) undernitrogen with stirring and treated with a solution of6-chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-carboxylicacid tert-butyl ester (118 mg, 0.33 mmol) in methanol (3 mL) and broughtto reflux for 18 hours. The mixture was cooled, concentrated, treatedwith H₂O and extracted with CH₂Cl₂. The organic layer was washed withsaturated NaCl solution and filtered through a cotton plug thenconcentrated to an oil (165 mg). (TLC: 5% methanol/CH₂Cl₂ R_(f) 0.55).

[0595] C)6-Methoxy-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-Pentaenehydrochloride

[0596]6-Methoxy-5,14-diazatetracyclo[10.3.10^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-carboxylicacid tert-butyl ester (138 mg, 0.41 mmol) was dissolved intrifluoroacetic acid (4 mL) brought to reflux for 4 hours. The mixturewas cooled and concentrated to an oil which was dissolved in ethylacetate and treated with 3N HCl/ethyl acetate (1 mL). Afterconcentration the residue was recrystallized from methanol/diethyl etherto provide a beige solid (51 mg, 26%). ¹H NMR (400 MHz, CD₃OD) δ8.77 (d,J=9.5 Hz, 1H), 8.01 (s, 1H), 7.90 (s, 1H), 7.54 (d, J=9.5 Hz, 1H), 4.30(s, 3H), 3.65 (br s, 1H), 3.61 (br s, 1H), 3.50 (dd, J=12.4, 3.8 Hz,2H), 3.29 (m, 2H), 2.44 (m, 1H), 2.24 (d, J=11.6 Hz, 1H). APCl MS m/e241.2 [(M+1)⁺]; M.p. 240, (darkens), 275° C. (dec.); (TLC: 10% methanol(NH₃)/CH₂Cl₂, R_(f) 0.38).

EXAMPLE 576-CHLORO-10-FLUORO-5,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE

[0597] A)1-(6-Chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone3-Fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]-dodeca-2(7),3,5-triene wasconverted to1-(3-Fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]-dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanoneby the methods described in Example 7A. This product was nitrated asdescribed in Example 7B. The resulting mixture of nitrated products wasreduced as described in Example 8, then converted to a chloroquinolineas described in Examples 54 and 55. These products were separated bycolumn chromatography on silica gel to provide the title compound. (TLC:50% ethyl acetate/hexanes, R_(f) 0.50).

[0598] B)6-Chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)lhexadeca-2(11),3,5,7,9-pentaenehydrochloride

[0599]1-(6-Chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanonewas converted to6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaeneby methods described in Example 7C. ¹H NMR (400 MHz, CDCl₃) δ8.03 (dd,J=8.5, 1.5 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.24 (s, 1H), 3.52 (br s,1H), 3.16 (br s, 1H), 3.11 (dd, J=12.8, 1.6 Hz, 2H), 2.97 (ddd, J=12.8,2.5, 2.5 Hz, 1H), 2.85 (ddd, J=12.8, 2.5, 2.5 Hz, 1H), 2.46 (m, 1H),2.06 (d, J=10.8 Hz, 1H). EI MS m/e 263 [M⁺]. This material was convertedto the title compound as described in Example 7C.

EXAMPLE585,8,14-TRIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,7,9-TETRAEN-6-ONEHYDROCHLORIDE

[0600] A)1-(5,8,14-Triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-on-10-yl)-2.2,2-trifluoro-ethanone

[0601]1-(4,5-Diamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(536 mg, 1.88 mmol) was stirred in ethanol (4 ml). This mixture wastreated with methyl-2-hydroxyl-2-methoxy acetate (0.203 mL, 2.07 mmol)and stirred at 70° C. for 2.5 hours. The reaction was cooled to roomtemperature and concentrated. Trituration with methanol and filtrationprovided light yellow solids (337mg, 55%). (TLC 10% methanol/CH₂Cl₂R_(f) 0.57).

[0602] B) 5,8,14-Triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-onehydrochloride

[0603] 1-(5,8,14-Triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-on-10-yl)-2,2,2-trifluoro-ethanone(145 mg, 0.45 mmol) was converted to the title compound by the methodsdescribed in Example 7C to provide a brown solid (26 mg, 46%). ¹H NMR(400 MHz, D₂O ) δ7.94 (s, 1H), 7.58 (s, 1H), 7.18 (s, 1H), 3.39 (br s,2H), 3.28 (br d, J=12.5 Hz, 1H), 3.12 (br d, J=12.5 Hz, 1H), 2.29 (m,1H), 1.99 (d, J=12.0 Hz, 1H). APCl MS m/e 228.2 [(M+1)⁺]; M.p. 296,(darkens), 310° C. (dec.); (TLC: 10% CH₂Cl₂/methanol(NH₃), R_(f) 0.10).

EXAMPLE 59 10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENE TOSYLATE

[0604] A) 3-N-Benzyl-2,3,4,5-tetrahydro-1,5-methano-1H-3-benzazepine

[0605] A stream of ozone was bubbled through a solution of 4.00 g ofbenzonorbornadiene (1,4-dihydro-1,4-methanonaphthalene) (28.1 mmol, 1.0equivalent) in 80 mL of methanol at −78° C. Once the solution developeda blue color, ozone generation was stopped after another few minutes andthen oxygen was bubbled through for five minutes to dispel the bluecolor. Then the solution was purged with nitrogen for 20 to 40 minutesto deoxygenate the solution. To the cold solution was added 0.199 g of5% platinum on carbon, 55% wet by weight, (.0281 mmol, 0.001equivalent). The system was passivated with hydrogen, pressurized to 40psi of hydrogen, and gradually warmed to room temperature. Once theozonide was reduced completely (within 45-60 minutes), an additional0.798 g of 5% platinum on carbon (0.112 mmol, 0.004 equivalent) wasadded to the reaction mixture at 0° C., followed by 3.07 mL ofbenzylamine (28.1 mmol, 1.0 equivalent) and 0.561 mL of 96% formic acid(14.0 mmol, 0.50 equivalent). The system was repressurized to 50 psi ofhydrogen and allowed to warm to room temperature. After 4 hours, thereaction mixture was removed from the reactor and filtered through a padof Celite, washing with 20 mL of methanol. This reaction mixture wasused in the next step (Example 59B), but isolation of the intermediatewas carried out as follows: the filtrate was concentrated in vacuo andpartitioned between 40 mL of methylene chloride and 30 mL of a saturatedaqueous solution of sodium carbonate; the aqueous layer was extractedwith another 30 mL of methylene chloride; the combined organic layerswere dried over anhydrous sodium sulfate and concentrated; the residuewas dissolved in 10 mL of 9:1 hexane/ethyl acetate and passed through aplug of silica gel; and after concentrating the filtrate, the titlecompound was obtained as an oil (3.34 g, 48%): ¹H NMR (400 MHz, CD₃OD):δ7.22-7.19 (m, 7H), 6.93 (d, J=8.0 Hz, 2H), 3.52 (s, 2H), 3.13-3.11 (m,2H), 2.85 (d, J=9.5 Hz, 2H), 2.47 (d, J=9.5 Hz, 2H), 2.32-2.29 (m, 1H),1.71 (d, J=10.0 Hz, 1H).

[0606] B) 2,3,4.5-Tetrahydro-1,5-methano-1H-3-benzazepine tosylate

[0607] A pressure reactor was charged with the crude3-N-benzyl-2,3,4,5-tetrahydro-1,5-methano-1H-3-benzazepine (from Example59A prior to workup) in 100 mL of methanol. To the reaction mixture wasadded 3.74 g of p-toluenesulfonic acid monohydrate (19.7 mmol, 0.7equivalent) and 0.986 g of 20% palladium hydroxide on carbon, 50% wet byweight (0.703 mmol, 0.025 equivalent). The reactor was pressurized to 50psi of hydrogen and heated to 40° C. After heating for 15 hours thereactor was cooled to room temperature. The reaction mixture wasfiltered through Celite, washing with methanol. The filtrate wasconcentrated in vacuo and stripped down from 20 mL of isopropanol. Theresidue was redissolved in 32 mL of isopropanol and heated to 70° C. Tothe hot solution was added 16 mL of hexane and the resulting solutionwas allowed to slowly cool with stirring. Crystals formed and werestirred at room temperature for 12 hours. The white crystals werefiltered and dried to give 2.65 g (28%) of the tosylate salt of2,3,4,5-tetrahydro-1,5-methano-1H-3-benzazepine tosylate; mp: 207-208 °C.; ¹H NMR (400 MHz, CD₃OD): δ7.69 (d, J=7.9 Hz, 2H), 7.43-7.32 (m, 4H),7.23 (d, J=7.9 Hz, 2H), 3.37 (d, J=11.2 Hz, 4H), 3.30 (bs, 2H), 3.15 (d,J=12.4 Hz, 2H), 2.36 (s, 3H), 2.40-2.35 (m, 1H), 2.08 (d, J=11.2 Hz,1H); ¹³C NMR (100 MHz, CD₃OD): δ140.8, 140.5, 139.1, 127.2, 127.2,124.3, 122.3, 45.1, 39.7, 37.3, 18.7; IR (KBr, cm⁻¹): 3438, 3021, 2958,2822, 2758, 2719, 2683, 2611, 2424, 1925, 1606, 1497, 1473, 1428, 1339,1302, 1259, 1228, 1219, 1176, 1160, 1137, 1122, 1087, 1078, 945, 914,876, 847, 829, 818, 801, 710, 492; Anal. Calcd for C₁₈H₂₁NO₃S: C, 65.23;H, 6.39; N, 4.23; Found: C, 65.05; H, 6.48; N, 4.26.

EXAMPLE 60 10-AZA-TRICYCLOf6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENE TOSYLATE

[0608] A) 3-Oxo-indan-1-carboxylic acid methyl ester

[0609] A solution of 10.0 g of 3-oxo-indan-1-carboxylic acid (56.8 mmol,1.0 equivalent) and 0.25 mL of concentrated sulfuric acid in 20 mL ofmethanol was heated to a reflux for 4 hours. The reaction mixture wasthen cooled to room temperature and diluted with 100 mL ofmethyl-tert-butyl alcohol. The organic solution was washed twice with 60mL of a saturated aqueous sodium bicarbonate solution, and once with 50mL of a saturated aqueous sodium chloride solution. The organic layerwas dried over anhydrous sodium sulfate and concentrated. The titlecompound crystallized as a white solid upon concentration, (10.4 g,96%); mp: 46-47° C.; ¹H NMR (400 MHz, CDCl₃): δ7.74 (d, J=7.6 Hz, 1H),7.68 (d, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H),4.29 (dd, J=8.0, 3.4 Hz, 1H), 3.76 (s, 3H), 3.13 (dd, J=19.1, 3.4 Hz,1H), 2.86 (dd, J=19.1, 8.0 Hz, 1H); ¹³C NMR (100 MHz, CD₃OD): δ204.4,172.5, 151.3, 136.5, 135.2, 129.1, 126.7, 124.1, 52.9, 43.8, 39.7; IR(neat, cm⁻¹): 2954, 1710, 1602, 1462, 1435, 1403, 1319, 1241, 1206,1168, 1092, 1044, 1014, 986, 881, 837, 760, 686, 580, 538.

[0610] B) 3-Cyano-3-trimethylsilanyloxy-indan-1-carboxylic acid methylester To a solution of 3.80 g of 3-oxo-indan-1-carboxylic acid methylester (20.0 mmol, 1 equivalent) in 6 mL of toluene and 2 mL ofacetonitrile was added 192 mg of zinc iodide (0.600 mmol, 0.03equivalent) followed by 3.47 mL of trimethylsilyl cyanide (26.0 mmol,1.3 equivalent). The reaction mixture was heated to 50° C. for 5 hours.The reaction mixture was then cooled to room temperature and dilutedwith 12 mL of toluene and 8 mL of a saturated aqueous sodium bicarbonatesolution. After stirring the mixture for 1 hour the layers wereseparated. The organic layer was washed with another 8 mL of a saturatedaqueous sodium bicarbonate solution followed by 8 mL of a saturatedaqueous sodium chloride solution. The organic layer was dried overanhydrous sodium sulfate and concentrated in vacuo to give3-cyano-3-trimethylsilanyloxy-indan-1-carboxylic acid methyl ester as anoil (5.61 g, 97%). The silylated cyanohydrin title compound was obtainedas a mixture of two diastereomers in a 2:1 ratio: ¹H NMR (400 MHz,CDCl₃): (major isomer) δ7.54-7.50 (m, 1H), 7.42-7.38 (m, 3H), 4.14 (t,J=7.7 Hz, 1H), 3.78 (s, 3H), 3.01 (dd, J=13.3, 7.5 Hz, 1H), 2.79 (dd,J=13.3, 7.5 Hz, 1H), 0.26 (s, 9H); (minor isomer) 67.59-7.55 (m, 1H),7.48-7.44 (m, 3H), 4.29 (t, J=7.5 Hz, 1H), 3.78 (s, 3H), 3.03 (dd,J=13.7, 7.5 Hz, 1H), 2.70 (dd, J=13.7, 7.5 Hz, 1H), 0.14 (s, 9H); ¹³CNMR (100 MHz, CDCl₃): (unassigned) δ172.3, 172.0, 142.3, 142.1, 140.1,138.8, 130.8, 130.5, 129.1, 128.9, 125.8, 125.6, 124.7, 124.3, 120.8,120.6, 75.4, 75.3, 52.7, 52.7, 47.4, 46.8, 45.6, 45.3, 1.4, 1.3; IR(neat, cm⁻¹ ): 2956, 1739, 1477, 1436, 1253, 1197, 1169, 1135, 1092,1033, 1011, 880, 843, 756, 623; Anal. Calcd for C₁₅H₁₉NO₃Si: C, 62.25;H, 6.62; N, 4.84; Found: C, 62.20; H, 6.53; N, 4.92.

[0611] C) 3-Aminomethyl-indan-1-carboxylic acid methyl ester

[0612] To a solution of 5.79 g of3-cyano-3-trimethylsilanyloxy-indan-1-carboxylic acid methyl ester (20.0mmol, 1.0 equivalent) in 25 mL of methanol was added 5.71 g ofp-toluenesulfonic acid monohydrate (30.0 mmol, 1.5 equivalent). Thesolution was stirred for 15 minutes and then 4.21 g of 20% palladiumhydroxide on carbon, 50% wet by weight, (3.00 mmol, 0.15 equivalent) wasadded. The reaction mixture was subjected to hydrogenolysis at 50 psi ofhydrogen over 24 hours. After this time, the reaction mixture wasfiltered through Celite and typically used filtrate in the next step(Example 60D). The isolation of the title compound was conducted asfollows: the filtrate was concentrated in vacuo; the residue waspartitioned between 30 mL of methylene chloride and 20 mL of a saturatedaqueous solution of sodium carbonate; the aqueous layer was extractedwith 15 mL of methylene chloride; the combined aqueous layers werewashed with 40 mL of a saturated aqueous solution of sodium chloride;the organic solution was dried over anhydrous sodium sulfate andconcentrated to afford the title compound as an oil (3.65 g, 89%) withapproximately a 10:1 ratio of diastereomers; (major diastereomer) ¹H NMR(400 MHz, CDCl₃): δ7.43 (dd, J=6.9, 1.6 Hz, 1H), 7.29-7.25 (m, 3H), 4.09(t, J=8.1 Hz, 1H), 3.80 (s, 3H), 3.31-3.24 (m, 1H), 3.14 (dd, J=12.8,4.7 Hz, 1H), 2.98 (dd, J=12.8, 7.3 Hz, 1H), 2.62-2.52 (m, 1H), 2.31-2.42(m, 1H), 1.3 (bs, 2H).

[0613] D) 9-Oxo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

[0614] To a solution of 3-aminomethyl-indan-1-carboxylic acid methylester (assume 20.0 mmol, 1 equivalent) in 50 mL of methanol (this wasthe crude reaction mixture from the prior step, Example 60C) was added3.84 g of sodium tert-butoxide (40.0 mmol, 2.0 equivalent). The reactionmixture was heated to a reflux for 2 hours. The reaction was cooled toroom temperature and concentrated in vacuo. The residue was partitionedbetween 60 mL of ethyl acetate and 40 mL of 5% aqueous solution ofsodium bicarbonate. The aqueous layer was extracted twice more with 50mL of ethyl acetate. The combined organic layers were dried overanhydrous sodium sulfate and concentrated to provide a solid material.Recrystallization of the solid from 10 mL of toluene provided whitecrystals of the title compound (1.78 g, 51%). mp =172-173° C.; ¹H NMR(400 MHz, CDCl₃): δ7.33 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.22(t, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 5.62 (s, 1H), 3.68 (dd,J=11.2, 4.1 Hz, 1H), 3.55 (d, J=3.7 Hz, 1H), 3.43-3.37 (m, 1H), 3.18 (d,J=11.2 Hz, 1H), 2.52-2.45 (m, 1H), 2.32 (d, J=11.2 Hz, 1H); ¹³C NMR (100MHz, CDCl₃): 6 173.6, 144.7, 144.6, 128.0, 127.7, 123.2, 122.9, 49.3,47.9, 39.1, 38.4; IR (neat, cm⁻¹): 3218, 2949, 2872, 1666, 1485, 1459,1400, 1328, 1303, 1288, 1250, 1215, 1122, 1104, 1045, 1004, 946, 910,756, 730, 643, 613; Anal. Calcd for C₁₁H1₂₁NO: C, 76.28; H, 6.40; N,8.09; Found: C, 75.94; H, 6.27; N, 7.99.

[0615] E) 10-Aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene tosylate

[0616] To a solution of 1.38 9 of9-oxo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene (8.00 mmol, 1equivalent) in 8 mL of tetrahydrofuran was added 603 mg of sodiumborohydride (16.0 mmol, 2.0 equivalent) followed by slow addition of2.77 mL of boron trifluoride diethyl etherate (21.6 mmol, 2.7equivalent). Once the effervescence subsided, the reaction mixture washeated to 50° C. for 5 hours. The reaction was then cooled to roomtemperature for addition of 10 mL of methanol (added dropwise at first)and 0.125 mL of concentrated hydrochloric acid. Heating was resumed at areflux for 12 hours. The reaction mixture was then cooled to roomtemperature and concentrated in vacuo. The residue was diluted with 20mL of 20% aqueous sodium hydroxide followed by 30 mL ofmethyl-tert-butyl ether. The mixture was stirred for 30 minutes and thenthe aqueous layer was extracted with another 30 mL of methyl-tert-butylether. The combined organic layers were washed with 40 mL of a saturatedaqueous sodium chloride solution and dried over anhydrous sodiumsulfate. After concentrating in vacuo, 1.67 g of p-toluenesulfonic acidmonohydrate (8.80 mmol, 1.1 equivalent) was added with 20 mL ofisopropanol. The solution was heated until homogeneous and then allowedto gradually cool to room temperature with stirring. White crystals ofthe title compound formed and were collected by filtration (2.17 g, 81%). mp: 207-208° C.; ¹H NMR (400 MHz, CD₃OD): δ7.69 (d, J=7.9 Hz, 2H),7.43-7.32 (m, 4H), 7.23 (d, J=7.9 Hz, 2H), 3.37 (d, J=11.2 Hz, 4H), 3.30(bs, 2H), 3.15 (d, J=12.4 Hz, 2H), 2.36 (s, 3H), 2.40-2.35 (m, 1H), 2.08(d, J=11.2 Hz, 1H); ¹³C NMR (100 MHz, CD₃OD): δ140.8, 140.5, 139.1,127.2, 127.2, 124.3, 122.3, 45.1, 39.7, 37.3, 18.7; IR (KBr, cm⁻¹):3438, 3021, 2958, 2822, 2758, 2719, 2683, 2611, 2424, 1925, 1606, 1497,1473, 1428, 1339, 1302, 1259, 1228, 1219, 1176, 1160, 1137, 1122, 1087,1078, 945, 914, 876, 847, 829, 818, 801, 710, 492; Anal. Calcd forC₁₈H₂₁NO₃S: C, 65.23; H, 6.39; N, 4.23; Found: C, 65.05; H, 6.48; N,4.26.

1. A compound selected from the group consisting of:(−)-5,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),9-trien-6-one;(−)-6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;(−)-2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-5-yl)-benzamide;(−)-6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;(−)-5-oxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;(−)-6-methyl-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;(−)-7-dimethylamino-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;(−)-5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;(−)-1-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;(−)-6-methyl-5-thia-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;(−)-6-methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(−)-7-methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(−)-6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(−)-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(−)-7-butyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(−)-6-methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(−)-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(−)-6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(−)-7-neopentyl-5,7,13-triazatetracyclo[9.3.10^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(−)-6-methyl-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(−)-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;(−)-6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;(−)-7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0^(2,10.0)^(4,8)]pentadeca-2,4(8),6,9-tetraene;(−)-5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one;and pharmaceutically acceptable salts thereof.
 2. A pharmaceuticalcomposition for use in reducing nicotine addiction or aiding in thecessation or lessening of tobacco use in a mammal, comprising an amountof a compound according to claim 1 that is effective in reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse and a pharmaceutically acceptable carrier.
 3. A method for reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse in a mammal, comprising administering to said mammal an amount of acompound according to claim 1 that is effective in reducing nicotineaddiction or aiding in the cessation or lessening of tobacco use.
 4. Apharmaceutical composition for treating a disorder or conditionselected. from inflammatory bowel disease, ulcerative colitis, pyodermagangrenosum, Crohn's disease, irritable bowel syndrome, spasticdystonia, chronic pain, acute pain, celiac sprue, pouchitis,vasoconstriction, anxiety, panic disorder, depression, bipolar disorder,autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS),cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiacarrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma,progressive supranuclear palsy; chemical dependencies and addictions;dependencies on, or addictions to, nicotine, tobacco products, alcohol,benzodiazepines, barbiturates, opioids or cocaine; headache, migraine,stroke, traumatic brain injury, obsessive-compulsive disorder,psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia,dyslexia, schizophrenia, multi-infarct dementia, age-related cognitivedecline, epilepsy, including petit mal absence epilepsy, senile dementiaof the Alzheimer's type, Parkinson's disease, attention deficithyperactivity disorder and Tourefte's Syndrome in a mammal, comprisingan amount of a compound according to claim 1 that is effective intreating such disorder or condition and a pharmaceutically acceptablecarrier.
 5. A method for treating a disorder or condition selected frominflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum,Crohn's disease, irritable bowel syndrome, spastic dystonia, chronicpain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety,panic disorder, depression, bipolar disorder, autism, sleep disorders,jet lag, amyotrophic lateral sclerosis, cognitive dysfunction,hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastricacid hypersecretion, ulcers, pheochromocytoma, progressive supranuclearpalsy; chemical dependencies and addictions; dependencies or, oraddictions to, nicotine, tobacco products, alcohol, benzodiazepines,barbiturates, opioids or cocaine; headache, migraine, stroke, traumaticbrain injury, obsessive-compulsive disorder, psychosis, Huntington'schorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia,multi-infarct dementia, age-related cognitive decline, epilepsy,including petit mal absence epilepsy, senile dementia of the Alzheimer'stype, Parkinson's disease, attention deficit hyperactivity disorder andTourette's Syndrome in a mammal, comprising administering to a mammal inneed of such treatment an amount of a compound according to claim 1 thatis effective in treating such disorder or condition.
 6. A pharmaceuticalcomposition for treating attention deficit hyperactivity disorder in amammal, comprising an amount of a compound according to claim 1 that iseffective in treating attention deficit hyperactivity disorder and apharmaceutically acceptable carrier.
 7. A method for treating attentiondeficit hyperactivity disorder in a mammal, comprising administering tosaid mammal an amount of a compound according to claim 1 that iseffective in attention deficit hyperactivity disorder.
 8. Apharmaceutical composition for treating Tourette's Syndrome in a mammal,comprising an amount of a compound according to claim 1 that iseffective in treating Tourette's Syndrome and a pharmaceuticallyacceptable carrier.
 9. A method for treating Tourette's Syndrome in amammal, comprising administering to said mammal an amount of a compoundaccording to claim 1 that is effective in treating Tourette's Syndrome.10. A compound selected from the group consisting of:(−)-4-methyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(−)-4-nitro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(−)-4-amino-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(−)-N¹-[10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl]acetamide;(−)-4-chloro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(−)-3-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-5-methyl-1,2,4-oxadiazole;(−)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ol;(−)-N⁴,N⁴-dimethyl-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonamide;(−)-4-(1-pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(−)-5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;(−)-4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(−)-5-ethynyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;(−)-5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;(−)-4-ethynyl-5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(−)-4-fluoro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(−)-4-chloro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(−)-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;(−)-4-ethynyl-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;and pharmaceutically acceptable salts thereof.
 11. A pharmaceuticalcomposition for use in reducing nicotine addiction or aiding in thecessation or lessening of tobacco use in a mammal, comprising an amountof a compound according to claim 10 that is effective in reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse and a pharmaceutically acceptable carrier.
 12. A method for reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse in a mammal, comprising administering to said mammal an amount of acompound according to claim 10 that is effective in reducing nicotineaddiction or aiding in the cessation or lessening of tobacco use.
 13. Apharmaceutical composition for treating a disorder or condition selectedfrom inflammatory bowel disease, ulcerative colitis, pyodermagangrenosum, Crohn's disease, irritable bowel syndrome, spasticdystonia, chronic pain, acute pain, celiac sprue, pouchitis,vasoconstriction, anxiety, panic disorder, depression, bipolar disorder,autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS),cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiacarrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma,progressive supranuclear palsy; chemical dependencies and addictions;dependencies on, or addictions to, nicotine, tobacco products, alcohol,benzodiazepines, barbiturates, opioids or cocaine; headache, migraine,stroke, traumatic brain injury, obsessive-compulsive disorder,psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia,dyslexia, schizophrenia, multi-infarct dementia, age-related cognitivedecline, epilepsy, including petit mal absence epilepsy, senile dementiaof the Alzheimer's type, Parkinson's disease, attention deficithyperactivity disorder and Tourette's Syndrome in a mammal, comprisingan amount of a compound according to claim 10 that is effective intreating such disorder or condition and a pharmaceutically acceptablecarrier.
 14. A method for treating a disorder or condition selected frominflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum,Crohn's disease, irritable bowel syndrome, spastic dystonia, chronicpain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety,panic disorder, depression, bipolar disorder, autism, sleep disorders,jet lag, amyotrophic lateral sclerosis, cognitive dysfunction,hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastricacid hypersecretion, ulcers, pheochromocytoma, progressive supranuclearpalsy; chemical dependencies and addictions; dependencies or, oraddictions to, nicotine, tobacco products, alcohol, benzodiazepines,barbiturates, opioids or cocaine; headache, migraine, stroke, traumaticbrain injury, obsessive-compulsive disorder, psychosis, Huntington'schorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia,multi-infarct dementia, age-related cognitive decline, epilepsy,including petit mal absence epilepsy, senile dementia of the Alzheimer'stype, Parkinson's disease, attention deficit hyperactivity disorder andTourette's Syndrome in a mammal, comprising administering to a mammal inneed of such treatment an amount of a compound according to claim 10that is effective in treating such disorder or condition.
 15. Apharmaceutical composition for treating attention deficit hyperactivitydisorder in a mammal, comprising an amount of a compound according toclaim 10 that is effective in treating attention deficit hyperactivitydisorder and a pharmaceutically acceptable carrier.
 16. A method fortreating attention deficit hyperactivity disorder in a mammal,comprising administering to said mammal an amount of a compoundaccording to claim 10 that is effective in attention deficithyperactivity disorder.
 17. A pharmaceutical composition for treatingTourette's Syndrome in a mammal, comprising an amount of a compoundaccording to claim 10 that is effective in treating Tourefte's Syndromeand a pharmaceutically acceptable carrier.
 18. A method for treatingTourette's Syndrome in a mammal, comprising administering to said mammalan amount of a compound according to claim 10 that is effective intreating Tourette's Syndrome.
 19. A compound selected from the groupconsisting of:(−)-3-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(−)-4-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(−)-3-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(−)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl cyanide;(−)-4-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene; andpharmaceutically acceptable salts thereof.
 20. A pharmaceuticalcomposition for use in reducing nicotine addiction or aiding in thecessation or lessening of tobacco use in a mammal, comprising an amountof a compound according to claim 19 that is effective in reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse and a pharmaceutically acceptable carrier.
 21. A method for reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse in a mammal, comprising administering to said mammal an amount of acompound according to claim 19 that is effective in reducing nicotineaddiction or aiding in the cessation or lessening of tobacco use.
 22. Apharmaceutical composition for treating a disorder or condition selectedfrom inflammatory bowel disease, ulcerative colitis, pyodermagangrenosum, Crohn's disease, irritable bowel syndrome, spasticdystonia, chronic pain, acute pain, celiac sprue, pouchitis,vasoconstriction, anxiety, panic disorder, depression, bipolar disorder,autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS),cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiacarrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma,progressive supranuclear palsy; chemical dependencies and addictions;dependencies on, or addictions to, nicotine, tobacco products, alcohol,benzodiazepines, barbiturates, opioids or cocaine; headache, migraine,stroke, traumatic brain injury, obsessive-compulsive disorder,psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia,dyslexia, schizophrenia, multi-infarct dementia, age-related cognitivedecline, epilepsy, including petit mal absence epilepsy, senile dementiaof the Alzheimer's type, Parkinson's disease, attention deficithyperactivity disorder and Tourette's Syndrome in a mammal, comprisingan amount of a compound according to claim 19 that is effective intreating such disorder or condition and a pharmaceutically acceptablecarrier.
 23. A method for treating a disorder or condition selected frominflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum,Crohn's disease, irritable bowel syndrome, spastic dystonia, chronicpain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety,panic disorder, depression, bipolar disorder, autism, sleep disorders,jet lag, amyotrophic lateral sclerosis, cognitive dysfunction,hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastricacid hypersecretion, ulcers, pheochromocytoma, progressive supranuclearpalsy; chemical dependencies and addictions; dependencies or, oraddictions to, nicotine, tobacco products, alcohol, benzodiazepines,barbiturates, opioids or cocaine; headache, migraine, stroke, traumaticbrain injury, obsessive-compulsive disorder, psychosis, Huntington'schorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia,multi-infarct dementia, age-related cognitive decline, epilepsy,including petit mal absence epilepsy, senile dementia of the Alzheimer'stype, Parkinson's disease, attention deficit hyperactivity disorder andTourette's Syndrome in a mammal, comprising administering to a mammal inneed of such treatment an amount of a compound according to claim 19that is effective in treating such disorder or condition.
 24. Apharmaceutical composition for treating attention deficit hyperactivitydisorder in a mammal, comprising an amount of a compound according toclaim 19 that is effective in treating attention deficit hyperactivitydisorder and a pharmaceutically acceptable carrier.
 25. A method fortreating attention deficit hyperactivity disorder in a mammal,comprising administering to said mammal an amount of a compoundaccording to claim 19 that is effective in attention deficithyperactivity disorder.
 26. A pharmaceutical composition for treatingTourette's Syndrome in a mammal, comprising an amount of a compoundaccording to claim 19 that is effective in treating Tourette's Syndromeand a pharmaceutically acceptable carrier.
 27. A method for treatingTourette's Syndrome in a mammal, comprising administering to said mammalan amount of a compound according to claim 19 that is effective intreating Tourette's Syndrome.
 28. A compound selected from the groupconsisting of:(−)-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(−)-6-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(−)-7-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(−)-7-ethyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(−)-8-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(−)-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one;(−)-6-chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(−)-6-methoxy-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(−)-6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(−)-6-chloro-3-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;and pharmaceutically acceptable salts thereof.
 29. A pharmaceuticalcomposition for use in reducing nicotine addiction or aiding in thecessation or lessening of tobacco use in a mammal, comprising an amountof a compound according to claim 28 that is effective in reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse and a pharmaceutically acceptable carrier.
 30. A method for reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse in a mammal, comprising administering to said mammal an amount of acompound according to claim 28 that is effective in reducing nicotineaddiction or aiding in the cessation or lessening of tobacco use.
 31. Apharmaceutical composition for treating a disorder or condition selectedfrom inflammatory bowel disease, ulcerative colitis, pyodermagangrenosum, Crohn's disease, irritable bowel syndrome, spasticdystonia, chronic pain, acute pain, celiac sprue, pouchitis,vasoconstriction, anxiety, panic disorder, depression, bipolar disorder,autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS),cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiacarrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma,progressive supranuclear palsy; chemical dependencies and addictions;dependencies on, or addictions to, nicotine, tobacco products, alcohol,benzodiazepines, barbiturates, opioids or cocaine; headache, migraine,stroke, traumatic brain injury, obsessive-compulsive disorder,psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia,dyslexia, schizophrenia, multi-infarct dementia, age-related cognitivedecline, epilepsy, including petit mal absence epilepsy, senile dementiaof the Alzheimer's type, Parkinson's disease, attention deficithyperactivity disorder and Tourette's Syndrome in a mammal, comprisingan amount of a compound according to claim 28 that is effective intreating such disorder or condition and a pharmaceutically acceptablecarrier.
 32. A method for treating a disorder or condition selected frominflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum,Crohn's disease, irritable bowel syndrome, spastic dystonia, chronicpain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety,panic disorder, depression, bipolar disorder, autism, sleep disorders,jet lag, amyotrophic lateral sclerosis, cognitive dysfunction,hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastricacid hypersecretion, ulcers, pheochromocytoma, progressive supranuclearpalsy; chemical dependencies and addictions; dependencies or, oraddictions to, nicotine, tobacco products, alcohol, benzodiazepines,barbiturates, opioids or cocaine; headache, migraine, stroke, traumaticbrain injury, obsessive-compulsive disorder, psychosis, Huntington'schorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia,multi-infarct dementia, age-related cognitive decline, epilepsy,including petit mal absence epilepsy, senile dementia of the Alzheimer'stype, Parkinson's disease, attention deficit hyperactivity disorder andTourette's Syndrome in a mammal, comprising administering to a mammal inneed of such treatment an amount of a compound according to claim 28that is effective in treating such disorder or condition.
 33. Apharmaceutical composition for treating attention deficit hyperactivitydisorder in a mammal, comprising an amount of a compound according toclaim 28 that is effective in treating attention deficit hyperactivitydisorder and a pharmaceutically acceptable carrier.
 34. A method fortreating attention deficit hyperactivity disorder in a mammal,comprising administering to said mammal an amount of a compoundaccording to claim 28 that is effective in attention deficithyperactivity disorder.
 35. A pharmaceutical composition for treatingTourette's Syndrome in a mammal, comprising an amount of a compoundaccording to claim 28 that is effective in treating Tourette's Syndromeand a pharmaceutically acceptable carrier.
 36. A method for treatingTourette's Syndrome in a mammal, comprising administering to said mammalan amount of a compound according to claim 28 that is effective intreating Tourette's Syndrome.